Hubbry Logo
Fibroblast growth factor receptor 1Fibroblast growth factor receptor 1Main
Open search
Fibroblast growth factor receptor 1
Community hub
Fibroblast growth factor receptor 1
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Fibroblast growth factor receptor 1
Fibroblast growth factor receptor 1
Fibroblast growth factor receptor 1
View on Wikipedia
from Wikipedia
FGFR1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFGFR1, BFGFR, CD331, CEK, FGFBR, FGFR-1, FLG, FLT-2, FLT2, HBGFR, HH2, HRTFDS, KAL2, N-SAM, OGD, bFGF-R-1, ECCL, fibroblast growth factor receptor 1
External IDsOMIM: 136350; MGI: 95522; HomoloGene: 69065; GeneCards: FGFR1; OMA:FGFR1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2260

14182

Ensembl

ENSG00000077782

ENSMUSG00000031565

UniProt

P11362

P16092

RefSeq (mRNA)

NM_001079908
NM_001079909
NM_010206

RefSeq (protein)

NP_001073377
NP_001073378
NP_034336

Location (UCSC)Chr 8: 38.4 – 38.47 MbChr 8: 26 – 26.07 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Fibroblast growth factor receptor 1 (FGFR-1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast growth factor family. FGFR-1 has been shown to be associated with Pfeiffer syndrome,[5] and clonal eosinophilias.[6]

Gene

[edit]

The FGFR1 gene is located on human chromosome 8 at position p11.23 (i.e. 8p11.23), has 24 exons, and codes for a Precursor mRNA that is alternatively spliced at exons 8A or 8B thereby generating two mRNAs coding for two FGFR1 isoforms, FGFR1-IIIb (also termed FGFR1b) and FGFR1-IIIc (also termed FGFR1c), respectively. Although these two isoforms have different tissue distributions and FGF-binding affinities, FGFR1-IIIc appears responsible for most of functions of the FGFR1 gene while FGFR1-IIIb appears to have only a minor, somewhat redundant functional role.[7][8] There are four other members of the FGFR1 gene family: FGFR2, FGFR3, FGFR4, and Fibroblast growth factor receptor-like 1 (FGFRL1). The FGFR1 gene, similar to the FGFR2-4 genes are commonly activated in human cancers as a result of their duplication, fusion with other genes, and point mutation; they are therefore classified as proto-oncogenes.[9]

Protein

[edit]

Receptor

[edit]

FGFR1 is a member of the fibroblast growth factor receptor (FGFR) family, which in addition to FGFR1, includes FGFR2, FGFR3, FGFR4, and FGFRL1. FGFR1-4 are cell surface membrane receptors that possess tyrosine kinase activity. A full-length representative of these four receptors consists of an extracellular region composed of three immunoglobulin-like domains which bind their proper ligands, the fibroblast growth factors (FGFs), a single hydrophobic stretch which passes through the cell's surface membrane, and a cytoplasmic tyrosine kinase domain. When bonded to FGFs, these receptors form dimers with any one of the four other FGFRs and then cross-phosphorylate key tyrosine residues on their dimer partners. These newly phosphorylated sites bind cytosolic docking proteins such as FRS2, PRKCG and GRB2 which proceed to activate cell signaling pathways that lead to cellular differentiation, growth, proliferation, prolonged survival, migration, and other functions. FGFRL1 lacks a prominent intracellular domain and tyrosine kinase activity; it may serve as a decoy receptor by binding with and thereby diluting the action of FGFs.[9][10] There are 18 known FGFs that bind to and activate one or more of the FGFRs: FGF1 to FGF10 and FGF16 to FGF23. Fourteen of these, FGF1 to FGF6, FGF8, FGF10, FGF17, and FGF19 to FGF23 bind and activate FGFR1.[11] FGFs binding to FGFR1 is promoted by their interaction with cell surface heparan sulfate proteoglycans and, with respect to FGF19, FGF20, and FGR23, the transmembrane protein Klotho.[11]

Cell activation

[edit]

FGFR1, when bound to a proper FGF, elicits cellular responses by activating signaling pathways that include the: a) Phospholipase C/PI3K/AKT, b) Ras subfamily/ERK, c) Protein kinase C, d) IP3-induced raising of cytosolic Ca2+, and e) Ca2+/calmodulin-activated elements and pathways. The exact pathways and elements activated depend on the cell type being stimulated plus other factors such as the stimulated cells microenvironment and previous as well as concurrent history of stimulation[9][10]

Figure 1. SH2 domains in complex with FGFR1 kinase. c-SH2 domain is colored in blue, n-SH2 domain is colored in red, and the interdomain linker is colored in yellow. FGFR1 kinase (green) interacts with n-SH2 domain at its C-terminal tail. The structure contains typical SH2 domain, with two α-helices and three antiparallel β-strands on each of the SH2 domains.

Activation of the gamma isoforms of phospholipase C (PLCγ) (see PLCG1 and PLCG2 illustrates one mechanism by which FGFR1 activates cell stimulating pathways. Following its binding of a proper FGF and subsequent pairing with another FGFR, FGFR1 becomes phosphorylated by its partner FGFR on a highly conserved tyrosine residue (Y766) at its C-terminal. This creates a binding or "docking" site to recruit PLCγ via PLCγ tandem nSH2 and cSH2 domains and then phosphorylate PLCγ. By being phosphorylated PLCγ is relieved of its auto-inhibition structure and becomes active in metabolizing nearby Phosphatidylinositol 4,5-bisphosphate (PIP2) to two secondary messengers, inositol 1,4,5-trisphosphate (IP3) and diacyglycerol (DAG). These secondary messengers proceed to mobilize other cell-signaling and cell-activating agents: IP3 elevates cytosolic Ca2+ and thereby various Ca2+-sensitive elements while DAG activates various protein kinase C isoforms.[11]

Recent publication on the 2.5 Å crystal structure of PLCγ in complex with FGFR1 kinase (PDB: 3GQI) provides new insights in understanding the molecular mechanism of FGFR1's recruitment of PLCγ by its SH2 domains. Figure 1 on the extreme right shows the PLCγ-FGFR1 kinase complex with the c-SH2 domain colored in red, n-SH2 domain colored in blue, and the interdomain linker colored in yellow. The structure contains typical SH2 domain, with two α-helices and three antiparallel β-strands in each SH2 domain. In this complex, the phosphorylated tyrosine (pY766) on the C-terminal tail of FGFR1 kinase binds preferentially to the nSH2 domain of PLCγ. The phosphorylation of tyrosine residue 766 on FGFR1 kinase forms hydrogen bonds with the n-SH2 to stabilize the complex. Hydrogen bonds in the binding pocket help to stabilize the PLCγ-FGFR1 kinase complex. The water molecule as shown mediates the interaction of asparagine 647 (N647) and aspartate 768 (D768) to further increase the binding affinity of the n-SH2 and FGFR1 kinase complex. (Figure 2). The phosphorylation of tyrosine 653 and tyrosine 654 in the active kinase conformation causes a large conformation change in the activation segment of FGFR1 kinase. Threonine 658 is moved by 24Å from the inactive form (Figure 3.) to the activated form of FGFR1 kinase (Figure 4.). The movement causes the closed conformation in the inactive form to open to enable substrate binding. It also allows the open conformation to coordinate Mg2+ with AMP-PCP (analog of ATP). In addition, pY653 and pY654 in the active form helps to maintain the open conformation of the SH2 and FGFR1 kinase complex. However, the mechanism by which the phosphorylation at Y653 and Y654 helps to recruit the SH2 domain to its C-terminal tail upon phosphorylation of Y766 remains elusive. Figure 5 shows the overlay structure of active and inactive forms of FGFR1 kinase. Figure 6 shows the dots and contacts on phosphorylated tyrosine residues 653 and 654. Green dots show highly favorable contacts between pY653 and pY654 with surrounding residues. Red spikes show unfavorable contacts in the activation segment. The figure is generated through Molprobity extension on Pymol.

Figure 8. Interface on the N-SH2 binding site and FGFR1 kinase. The FGFR1 kinase is bound to the N-SH2 domain primarily through charged amino acids. The acid base pair (D755 and R609) located in the middle of the interface are nearly parallel to each other, indicating a highly favorable interaction.

The tyrosine kinase region of FGFR1 binds to the N-SH2 domain of PLCγ primarily through charged amino acids. Arginine residue (R609) on the N-SH2 domain forms a salt bridge to aspartate 755 (D755) on the FGFR1 domain. The acid base pairs located in the middle of the interface are nearly parallel to each other, indicating a highly favorable interaction. The N-SH2 domain makes an additional polar contact through water-mediated interaction that takes place between the N-SH2 domain and the FGFR1 kinase region. The arginine residue 609 (R609) on the FGFR1 kinase also forms a salt bridge to the aspartate residue (D594) on the N-SH2 domain. The acid-base pair interacts with each other carry out a reduction–oxidation reaction that stabilizes the complex (Figure 7). Previous studies have done to elucidate the binding affinity of the n-SH2 domain with the FGFR1 kinase complex by mutating these phenylalanine or valine amino acids. The results from isothermal titration calorimetry indicated that the binding affinity of the complex decreased by 3 to 6-fold, without affecting the phosphorylation of the tyrosine residues.[12]

Cell inhibition

[edit]

FGF-induced activation of FGFR1 also stimulates the activation of sprouty proteins SPRY1, SPRY2, SPRY3, and/or SPRY4 which in turn interact with GRB2, SOS1, and/or c-Raf to reduce or inhibit further cell stimulation by activated FGFR1 as well as other tyrosine kinase receptors such as the Epidermal growth factor receptor. These interactions serve as negative feedback loops to limit the extent of cellular activation.[11]

Function

[edit]

Mice genetically engineered to lack a functional Fgfr1 gene (ortholog of the human FGFR1 gene) die in utero before 10.5 days of gestation. Embryos exhibit extensive deficiencies in the development and organization of mesoderm-derived tissues and the musculoskeletal system. The Fgfr1 gene appears critical for the truncation of embryonic structures and formation of muscle and bone tissues and thereby the normal formation of limbs, skull, outer, middle, and inner ear, neural tube, tail, and lower spine as well as normal hearing.[11][13][14]

Clinical significance

[edit]

Congenital diseases

[edit]

Hereditary mutations in the FGFR1 gene are associated with various congenital malformations of the musculoskeletal system. Interstitial deletions at human chromosome 8p12-p11, arginine to a stop nonsense mutation at FGFR1 amino acid 622 (annotated as R622X), and numerous other autosomal dominant inactivating mutations in FGFR1 are responsible for ~10% of the cases of Kallmann syndrome. This syndrome is a form of hypogonadotropic hypogonadism associated in a varying percentage of cases with anosmia or hyposmia; cleft palate and other craniofacial defects; and scoliosis and other musculoskeletal malformations. An activating mutation in FGFR1 viz., P232R (proline-to-arginine substitution in the protein's 232nd amino acid), is responsible for the Type 1 or classic form of Pfeiffer syndrome, a disease characterized by craniosynostosis and mid-face deformities. A tyrosine-to-cysteine substitution mutation in the 372nd amino acid of FGFR1 (Y372C) is responsible for some cases of Osteoglophonic dysplasia. This mutation results in craniosynostosis, mandibular prognathism, hypertelorism, brachydactyly, and inter-phalangeal joint fusion. Other inherited defects associated with 'FGFR1 mutations likewise involve musculoskeletal malformations: these include the Jackson–Weiss syndrome (proline to arg substitution at amino acid 252), Antley-Bixler syndrome (isoleucine-to-threonine at amino acid 300 (I300T), and trigonocephaly (mutation the same as the one for the Antley-Bixler syndrome viz., I300T).[10][11][15]

Cancers

[edit]

Somatic mutations and epigenetic changes in the expression of the FGFR1 gene occur in and are thought to contribute to various types of lung, breast, hematological, and other types of cancers.

Lung cancers

[edit]

Amplification of the FGFR1 gene (four or more copies) is present in 9 to 22% of patients with non-small-cell lung carcinoma (NSCLC). FGFR1 amplification was highly correlated with a history of tobacco smoking and proved to be the single largest prognostic factor in a cohort of patients suffering this disease. About 1% of patients with other types of lung cancer show amplifications in FGFR1.[9][10][16][17]

Breast cancers

[edit]

Amplification of FGFR1 also occurs in ~10% of estrogen receptor positive breast cancers, particularly of the luminal subtype B form of breast cancer. The presence of FGFR1 amplification has been correlated with resistance to hormone blocking therapy and found to be a poor prognostic factor in the disease.[9][10]

Hematological cancers

[edit]

In certain rare hematological cancers, the fusion of FGFR1 with various other genes due to Chromosomal translocations or Interstitial deletions create genes that encode chimeric FGFR1 Fusion proteins. These proteins have continuously active FGFR1-derived tyrosine kinase and thereby continuously stimulated the cell growth and proliferation. These mutations occur in the early stages of myeloid and/or lymphoid cell lines and are the cause of or contribute to the development and progression of certain types of hematological malignancies that have increased numbers of circulating blood eosinophils, increased numbers of bone marrow eosinophils, and/or the infiltration of eosinophils into tissues. These neoplasms were initially regarded as eosinophilias, hypereosinophilias, Myeloid leukemias, myeloproliferative neoplasms, myeloid sarcomas, lymphoid leukemias, or non-Hodgkin lymphomas. Based on their association with eosinophils, unique genetic mutations, and known or potential sensitivity to tyrosine kinase inhibitor therapy, they are now being classified together as clonal eosinophilias.[6] These mutations are described by connecting the chromosome site for the FGFR1 gene, 8p11 (i.e. human chromosome 8's short arm [i.e. p] at position 11) with another gene such as the MYO18A whose site is 17q11 (i.e human chromosome 17's long arm [i.e. q] at position 11) to yield the fusion gene annotated as t(8;17)(p11;q11). These FGFR1 mutations along with the chromosomal location of FGFR1A's partner gene and the annotation of the fused gene are given in the following table.[18][19][20]

Gene locus notation gene locus notation Gene locus notation gene locus notation gene locus notation
MYO18A 17q11 t(8;17)(p11;q11) CPSF6 12q15 t(8;12)(p11;q15) TPR 1q25 t(1;8)(q25p11;; HERV-K 10q13 t(8;13)(p11-q13) FGFR1OP2 12p11 t(8;12)(p11;q12)
ZMYM2 13q12 t(8;13)(p11;q12) CUTL1 7q22 t(7;8)(q22;p11) SQSTM1 5q35 t(5;8)(q35;p11 RANBP2 2q13 t(2;8)(q13;p11) LRRFIP1 2q37 t(8;2)(p11;q37)
CNTRL 9q33 t(8;9)(p11;q33) FGFR1OP 6q27 t(6;8)(q27;p11) BCR 22q11 t(8;22)(p11;q11 NUP98 11p15 t(8;11)(p11-p15) MYST3 8p11.21 multiple[21]
CEP110 16p12 t(8;16)(p11;p12)

These cancers are sometimes termed 8p11 myeloproliferative syndromes based on the chromosomal location of the FGFR1 gene. Translocations involving ZMYM2, CNTRL, and FGFR1OP2 are the most common forms of these 8p11 syndromes. In general, patients with any of these diseases have an average age of 44 and present with fatigue, night sweats, weight loss, fever, lymphadenopathy, and enlarged liver and/or spleen. They typically evidence hematological features of the myeloproliferative syndrome with moderate to greatly elevated levels of blood and bone marrow eosinophils. However, patients bearing: a) ZMYM2-FGFR1 fusion genes often present as T-cell lymphomas with spreading to non-lymphoid tissue; b) FGFR1-BCR fusion genes usually present as chronic myelogenous leukemias; c) CEP110 fusion genes may present as a chronic myelomonocytic leukemia with involvement of tonsil; and d) FGFR1-BCR or FGFR1-MYST3 fusion genes often present with little or no eosinophilia. Diagnosis requires conventional cytogenetics using Fluorescence in situ hybridization#Variations on probes and analysis for FGFR1.[19][21]

Unlike many other myeloid neoplasms with eosinophil such as those caused by Platelet-derived growth factor receptor A or platelet-derived growth factor receptor B fusion genes, the myelodysplasia syndromes caused by FGFR1 fusion genes in general do not respond to tyrosine kinase inhibitors, are aggressive and rapidly progressive, and require treatment with chemotherapy agents followed by bone marrow transplantion in order to improve survival.[19][18] The tyrosine kinase inhibitor Ponatinib has been used as mono-therapy and subsequently used in combination with intensive chemotherapy to treat the myelodysplasia caused by the FGFR1-BCR fusion gene.[19]

Phosphaturic mesenchymal tumor

[edit]

Phosphaturic mesenchymal tumors is characterized by a hypervascular proliferation of apparently non-malignant spindled cells associated with a variable amount of ‘smudgy’ calcified matrix but a small subset of these tumors exhibit malignant histological features and may behave in a clinically malignant fashion. In a series of 15 patients with this disease, 9 were found to have tumors that bore fusions between the FGFR1 gene and the FN1 gene located on human chromosome 2 at position q35.[22] The FGFR1-FN1 fusion gene was again identified in 16 of 39 (41%) patients with phosphaturic mesenchymal tumors.[23] The role of the(2;8)(35;11) FGFR1-FN1 fusion gene in this disease is not known.

Rhabdomyosarcoma

[edit]

Elevated expression of FGFR1 protein was detected in 10 of 10 human Rhabdomyosarcoma tumors and 4 of 4 human cell lines derived from rhabdomyocarcoma. The tumor cases included 6 cases of Alveolar rhabdomyosarcoma, 2 cases of Embryonal rhabdomyosarcoma, and 2 cases of pleomorphic rhabdomyosarcoma. Rhabdomyosarcoma is a highly malignant form of cancer that develops from immature skeletal muscle cell precursors viz., myoblastss that have failed to fully differentiate. FGFR1 activation causes myoblast to proliferate while inhibiting their differentiation, dual effects that may lead to the assumption of a malignant phenotype by these cells. The 10 human rhabdomyosarcoma tumor exhibited decreased levels of methylation of CpG islands upstream of the first FGFR1 exon. CpG islands commonly function to silence expression of adjacent genes while their methylation inhibits this silencing. Hypomethylation of CpG islands upstream of FGFR1 is hypothesized to be at least in part responsible for the over-expression of FGFR1 by and malignant behavior of these rhabdomyosarcoma tumors.[24] In addition, a single case of rhabdomyosarcoma tumor was found express co-amplified FOXO1 gene at 13q14 and FGFR1 gene at 8p11, i.e. t(8;13)(p11;q14), suggesting the formation, amplification, and malignant activity of a chimerical FOXO1-FGFR1 fusion gene by this tumor.[9][25]

Other types of cancers

[edit]

Acquired abnormalities if the FGFR1 gene are found in: ~14% of urinary bladder Transitional cell carcinomas (almost all are amplifications); ~10% of squamous cell Head and neck cancers (~80% amplifications, 20% other mutations); ~7% of endometrial cancers (half amplifications, half other types of mutations); ~6% of prostate cancers (half amplifications, half other mutations); ~5% of ovarian Papillary serous cystadenocarcinoma (almost all amplifications); ~5% of colorectal cancers (~60 amplifications, 40% other mutations); ~4% of sarcomas (mostly amplifications); <3% of Glioblastomas (Fusion of FGFR1 and TACC1 (8p11) gene); <3% of Salivary gland cancer (all amplifications); and <2% in certain other cancers.[11][26][27]

FGFR inhibitors

[edit]

FGFR-targeted drugs exert direct as well as indirect anticancer effects, due to the fact that FGFRs on cancer cells and endothelial cells are involved in tumorigenesis and vasculogenesis, respectively.[9] FGFR therapeutics are active as FGF affects numerous features of cancers, such as invasiveness, stemness and cellular survival. Primary among such drugs are antagonists. Small molecules that fit between the ATP binding pockets of the tyrosine kinase domains of the receptors. For FGFR1, numerous such small molecules have been approved for targeting the TKI ATP pocket. These include dovitinib and brivanib. The table below provides the IC50 (nanomolar) of small-molecule compounds targeting FGFRs.[9]

PD173074 Dovitinib Ki23057 Lenvatinib Brivanib Nintedanib Ponatinib MK-2461 Lucitanib AZD4547
26 8 NA 46 148 69 2.2 65 18 0.2

FGFR1 mutation in breast and lung cancer as a result of genetic over-amplification is effectively targeted using dovitinib and ponatinib, respectively.[28] Drug resistance is a highly relevant topic in the field of drug development for FGFR targets. FGFR inhibitors allow for the increase of tumor sensitivity to cytotoxic anticancer drugs such as paclitaxel, and etoposide in human cancer cells, thereby decreasing antiapoptotic potential based on faulty FGFR activation.[9] Since FGF signaling inhibition dramatically reduces revascularization, it interferes with one of the hallmarks of cancers, angiogenesis. It also reduces tumor burden in human tumors that depend on autocrine FGF signaling, based on FGF2 upregulation following the common VEGFR-2 therapy for breast cancer. Thus, FGFR1 can act synergistically with therapies to cut off cancer clonal resurgence by eliminating potential pathways of future relapse. Moreover, FGF signaling inhibition dramatically reduces revascularization.[29][30]

FGFR inhibitors have been predicted to be effective on relapsed tumors because of the clonal evolution of an FGFR-activated minor subpopulation after therapy targeted to EGFRs or VEGFRs. Because there are multiple mechanisms of action for FGFR inhibitors to overcome drug resistance in human cancer, FGFR-targeted therapy might be a promising strategy for the treatment of refractory cancer.[31]

AZD4547 has undergone a phase II clinical trial in gastric cancer and reported some results.[32]

Lucitanib is an inhibitor of FGFR1 and FGFR2 and has undergone clinical trials for advanced solid tumors.[33]

Dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, has had a clinical trial on FGFR-amplified breast cancers.[28]

Interactions

[edit]

Fibroblast growth factor receptor 1 has been shown to interact with:

See also

[edit]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Fibroblast growth factor receptor 1

View on Grokipedia
from Grokipedia
Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase encoded by the FGFR1 gene located on chromosome 8p11.23, consisting of 19 exons and producing a transmembrane protein essential for cellular signaling. This protein binds fibroblast growth factors (FGFs), such as FGF1 and FGF2, to regulate key processes including cell proliferation, differentiation, migration, survival, and angiogenesis, playing a pivotal role in embryonic development, organogenesis, tissue repair, and wound healing. Structurally, FGFR1 features an extracellular region with three immunoglobulin-like domains (D1–D3), an acidic box, and a heparin-binding site, connected to a single and an intracellular domain divided by a kinase insert. in the D3 domain generates tissue-specific isoforms (IIIb and IIIc) that determine -binding specificity, with IIIb predominant in epithelial tissues and IIIc in mesenchymal cells. binding, facilitated by proteoglycans, induces receptor dimerization, autophosphorylation of residues, and activation of downstream pathways including RAS/MAPK/ERK for proliferation, PI3K/AKT for survival, and PLCγ for calcium mobilization. Physiologically, FGFR1 is ubiquitously expressed but particularly abundant in tissues like the , adipose, and , where it supports regeneration, neuronal migration (e.g., neurons), vascular development, and metabolic . Dysregulation via gain-of-function mutations (e.g., P252R in causing and ), loss-of-function variants (e.g., in leading to and ), gene fusions (e.g., in 8p11 myeloproliferative syndrome), or amplifications contributes to congenital disorders like osteoglophonic dysplasia and Hartsfield syndrome, as well as cancers including , , and pancreatic tumors.

Genetics

Gene Structure and Location

The FGFR1 gene is located on the short arm of human chromosome 8 at cytogenetic band 8p11.23, specifically spanning genomic coordinates 38,400,215 to 38,468,834 on the reverse strand (GRCh38 assembly). The gene encompasses approximately 69 kb of genomic DNA and contains 21 exons in total, with the canonical transcript (ENST00000447712.7) comprising 18 exons, 17 of which are coding. The promoter region of FGFR1, situated in the 5'-flanking sequence upstream of exon 1, includes multiple Sp1 and Sp3 binding sites that drive basal transcription activity in various cell types. These cis-regulatory elements interact with transcription factors to maintain constitutive expression levels, with additional regulatory features such as structures identified within approximately 1.4 kb of the transcription start site (-1300/+100 bp) that influence FGFR1 expression in contexts like . The FGFR1 gene exhibits high evolutionary conservation across vertebrate species, including mammals, birds, and , with preserved exon-intron and key coding sequences in the extracellular and domains essential for receptor function. This conservation extends to expression patterns during embryonic development, where FGFR1 orthologs play analogous roles in patterning and from to humans. Chromosomal aberrations, particularly translocations involving the FGFR1 locus at 8p11.23 that generate fusion genes (e.g., with partners like ZNF198 or BCR), are characteristic of 8p11 myeloproliferative syndrome, a rare disorder leading to aggressive hematologic malignancies.

Isoforms and Expression Patterns

The FGFR1 gene produces two primary isoforms through of III, which encodes the carboxyl-terminal half of the third immunoglobulin-like domain. This splicing generates the FGFR1-IIIb and FGFR1-IIIc variants, which differ in their ligand-binding specificities and tissue distribution. The IIIb isoform is epithelial-specific and binds with high affinity to fibroblast growth factors (FGFs) 1, 3, 7, and 10, while the IIIc isoform is mesenchymal-specific and preferentially binds FGFs 1, 2, 4, and 5. These differences arise from distinct sequences in the IIIb and IIIc exons, enabling tissue-appropriate FGF signaling responses. Expression of FGFR1 isoforms follows tissue-specific patterns that align with their functional roles. In embryonic development, FGFR1 shows high expression in mesodermal and mesenchymal tissues, including the developing and , as revealed by in E14.5 mouse embryos. In adult humans, RNA-seq analyses from the GTEx consortium indicate elevated FGFR1 mRNA levels across multiple tissues, with notably high expression in the (e.g., cortex and ), cortex, and , where median transcripts per million (TPM) values often exceed 20-50. These patterns reflect FGFR1's broad involvement in tissue maintenance and repair. Post-transcriptional regulation of FGFR1 expression is mediated by microRNAs (miRNAs) that target its mRNA. For instance, miR-214-3p binds to the 3' of FGFR1 mRNA, promoting its degradation and reducing protein levels in various cell types. Similarly, miR-1 and miR-133a repress FGFR1 translation in adult cardiomyocytes, preventing aberrant signaling and cell dedifferentiation. Such miRNA interactions fine-tune FGFR1 availability in response to cellular contexts.

Protein Structure

Domain Organization

The fibroblast growth factor receptor 1 (FGFR1) protein is a single-pass transmembrane characterized by a modular domain organization that facilitates its role in cell surface signaling. The canonical isoform, FGFR1-IIIc, comprises 822 with a calculated molecular weight of approximately 91.8 kDa, though post-translational modifications such as increase the observed mass to around 92 kDa. The extracellular region, spanning residues 23 to 369, includes three immunoglobulin-like (Ig-like) domains: D1 (residues 33–124), D2 (residues 143–240), and D3 (residues 251–360), connected by a short acidic linker region (acid box, residues 125–142) between D1 and D2, and a flexible linker between D2 and D3. The D2 and D3 domains form the primary ligand-binding core, while D1 contributes to . Each Ig-like domain is stabilized by a conserved intramolecular bond (e.g., Cys52–Cys99 in D1, Cys155–Cys204 in D2, and Cys279–Cys336 in D3), and the extracellular domain features multiple N-linked sites, including Asn99, Asn173, and Asn328, which influence folding and trafficking. structures, such as PDB ID 1CVS, reveal the dimeric arrangement of the D2–D3 segment, highlighting the β-sheet-rich folds typical of Ig domains. Anchoring the protein to the is a single α-helical , consisting of approximately 22 hydrophobic residues from ~370 to 390, which enables dimerization upon stimulation through motifs like GxxxG-like sequences. This segment transitions into the intracellular juxtamembrane region (residues ~398–464), a flexible linker that connects the to the catalytic core and contains key regulatory residues. The intracellular portion, encompassing residues 465 to 822, features a bilobed domain (TKD, residues 458–765) characteristic of receptor , with an N-terminal lobe (β-sheet rich) and a C-terminal lobe (α-helical) split by a hinge region that accommodates ATP binding. The TKD is preceded by the juxtamembrane segment and followed by a short C-terminal tail (residues 766–822) lacking enzymatic activity but involved in regulatory interactions. Structural insights from PDB entries like 1FGK illustrate the autoinhibited conformation of the FGFR1 TKD, with conserved motifs such as the activation loop (residues 647–657) poised for . No bonds are present intracellularly, but the domain's stability relies on hydrophobic interactions and hydrogen bonding within the lobes. in the extracellular region can produce isoforms lacking D1 or altering the D3 exon, potentially modulating domain organization without affecting the core transmembrane or intracellular architecture.

Ligand Binding and Receptor Dynamics

Fibroblast growth factor receptor 1 (FGFR1) exhibits high-affinity binding to a subset of the 18 known fibroblast growth factors (FGFs), typically ranging from 7 to 14 ligands depending on isoform and context, with prominent examples including FGF1 and FGF2 that initiate . These interactions occur primarily through the extracellular immunoglobulin-like domains 2 and 3 (D2 and D3) of FGFR1, where FGF ligands engage specific residues to achieve binding affinities in the range of 10-100 nM, as measured by techniques such as . For instance, the (Kd) for FGF2-FGFR1 is approximately 62 nM, while FGF1-FGFR1 binding yields a Kd of about 136 nM. Heparan sulfate proteoglycans (HSPGs) serve as essential co-receptors that dramatically enhance FGF-FGFR1 binding affinity by stabilizing the ligand and facilitating ternary complex formation, often increasing avidity by orders of magnitude through ionic interactions between sulfated HS chains and basic residues on both FGF and FGFR1. In the absence of HSPGs, binary FGF-FGFR1 complexes form with moderate affinity, but HSPG co-binding promotes the assembly of a functional 2:2 FGF-FGFR-HS dimer, where two FGF molecules bridge two FGFR1 ectodomains via contacts involving the D2-D3 linker and adjacent surfaces. This dimerization model, elucidated from crystal structures, relies on symmetric or near-symmetric arrangements that position the transmembrane and kinase domains for subsequent activation. Upon binding, FGFR1 undergoes conformational shifts that transition from an autoinhibited monomeric state to an asymmetric dimer, in which one receptor molecule acts as an allosteric activator to enhance the activity of its partner through inter-lobe contacts in the intracellular domain. This asymmetry ensures efficient trans-autophosphorylation while preventing symmetric inactive dimers, as supported by structural analyses showing one active conformation amid subtle extracellular rearrangements. Recent cryo-EM studies, such as those resolving FGFR1 complexes with FGF analogs, further illustrate these dynamics, highlighting how environmental factors like modulate HS-mediated contacts to fine-tune dimer stability.

Signaling Pathways

Activation Mechanisms

The activation of fibroblast growth factor receptor 1 (FGFR1) is initiated by the binding of fibroblast growth factors (FGFs) in complex with proteoglycans, which induces receptor dimerization on the cell surface. This ligand-induced dimerization brings two FGFR1 molecules into close proximity, facilitating structural rearrangements in the transmembrane and juxtamembrane domains that position the intracellular domains for trans-autophosphorylation. Specifically, the juxtamembrane segment undergoes a conformational shift, stabilizing the dimer and enabling the kinase domains to adopt an orientation conducive to without requiring complete symmetric alignment. Upon dimerization, the FGFR1 kinase domains engage in a sequential autophosphorylation cascade, beginning with tyrosine residues in the activation loop. Phosphorylation first occurs at Y653, which partially activates the kinase by enhancing catalytic activity approximately 50- to 100-fold. Subsequent phosphorylations proceed in a precise order: Y583 in the kinase insert, Y463 in the juxtamembrane domain, Y766 in the C-terminal tail, Y585 in the kinase insert, and finally Y654 in the activation loop, with phosphorylation of Y654 contributing to the overall 500- to 1,000-fold amplification in activity; Y730 in the kinase domain is an additional site exhibiting lower stoichiometry. This ordered process is mediated by trans-phosphorylation between the dimerized kinases, with rate constants decreasing progressively (e.g., 0.054 s⁻¹ for Y653 and 0.004 s⁻¹ for Y654). The ATP-binding pocket in the FGFR1 domain undergoes dynamic rearrangements during , with the aspartate-phenylalanine-glycine (DFG) motif flipping from an inactive DFG-out to an active DFG-in conformation to accommodate ATP binding and coordination. This transition is energetically demanding, creating a high free-energy barrier that ensures tight . proceeds asymmetrically, where one molecule acts as the "" (its N-lobe interacting with the C-lobe of the partner "substrate" molecule), promoting efficient trans-autophosphorylation without full symmetric dimerization of the domains. Quantitative models indicate that FGFR1 dimers form transiently with occurring on the order of minutes, as evidenced by signaling peaks within 2-5 minutes and dimer dissociation contributing to signal termination around 20-30 minutes post-stimulation.

Downstream Signaling Cascades

Upon ligand-induced dimerization and autophosphorylation, FGFR1 initiates multiple intracellular signaling cascades that propagate signals for cellular proliferation, , and differentiation. These pathways are primarily activated through the of adaptor proteins and enzymes to specific sites on the receptor's intracellular domain. The RAS-MAPK/ERK pathway is a central downstream effector of FGFR1, primarily mediated by the adaptor protein FRS2α, which binds constitutively to the juxtamembrane region of FGFR1. Upon FGFR1 , FRS2α becomes -, recruiting the GRB2-SOS complex that activates RAS, leading to sequential and of RAF, MEK, and ERK kinases. This cascade culminates in ERK translocation to the nucleus, where it transcription factors such as ELK1, promoting associated with cell proliferation and differentiation. Parallel to the MAPK pathway, FGFR1 activates the PI3K-AKT-mTOR axis, which supports cell survival and inhibits . Phosphorylation of specific FGFR1 tyrosines recruits PI3K via direct binding or through adaptors like FRS2α and , generating PIP3 that recruits and activates AKT at the plasma membrane. Activated AKT then phosphorylates targets such as BAD and FOXO, suppressing pro-apoptotic signals, while also activating to enhance protein synthesis and cell growth. The PLCγ pathway is triggered by phosphorylation of tyrosine 766 (Y766) on FGFR1, which serves as a docking site for the PLCγ . Activated PLCγ hydrolyzes PIP2 into IP3 and DAG; IP3 mobilizes intracellular Ca²⁺ stores, while DAG activates PKC isoforms, influencing cytoskeletal dynamics and gene expression. Additionally, FGFR1 signaling engages and transcription factors, which are phosphorylated either directly by the receptor or via JAK kinases, leading to their dimerization and nuclear translocation for target gene regulation. This pathway exhibits crosstalk with other receptor tyrosine kinases (RTKs), such as EGFR, amplifying transcriptional responses in contexts like . Beyond canonical pathways, non-canonical FGFR1 signaling, including endocytic trafficking-dependent mechanisms, has been implicated in regulating developmental processes such as induction (as of 2024). Temporal dynamics of FGFR1 signaling are characterized by rapid activation, with ERK phosphorylation peaking at 5-10 minutes post-stimulation before attenuation, ensuring transient and context-specific cellular responses.

Regulatory Inhibition

Regulatory inhibition of FGFR1 signaling is essential to prevent excessive activation and maintain cellular , primarily through intrinsic feedback mechanisms and extrinsic modulators that attenuate receptor activity at multiple levels. One key intrinsic mechanism involves the induction of Sprouty (Spry) proteins, such as Spry1 and Spry2, which are transcriptionally upregulated as part of a loop following FGFR1 activation and ERK signaling. These proteins translocate to the plasma membrane, where they bind to and disrupt the Grb2-Sos complex, thereby inhibiting Ras activation downstream of the FGFR1 adaptor protein FRS2. This blockade specifically dampens the Ras-ERK pathway without affecting other branches like PLCγ, ensuring precise control of mitogenic signaling. The upregulation of Spry proteins occurs rapidly, typically within 15-30 minutes of FGF stimulation, allowing timely attenuation of the response. Another intrinsic regulatory process targets the FGFR1 receptor itself through of specific serine residues in its C-terminal tail, which promotes receptor internalization and signal termination. For instance, serine 777 (S777) is phosphorylated by ERK1/2 in a direct manner upon FGFR1 activation, reducing phosphorylation in the kinase domain and facilitating clathrin-mediated . This phosphorylation event enhances the receptor's trafficking to early endosomes, where signaling is curtailed before lysosomal degradation, thereby limiting the duration of downstream cascades. at S777, such as S777A, prolong FGFR1 phosphorylation and signaling, underscoring its role in feedback attenuation. FGFR1 downregulation also occurs via post-translational modifications, including Cbl-mediated ubiquitination, which directs the receptor to lysosomal degradation pathways. The E3 Cbl is recruited to activated FGFR1 through interactions with FRS2 and , leading to polyubiquitination of residues in the receptor's intracellular domain. This ubiquitination serves as a sorting signal, promoting FGFR1 delivery from early endosomes to lysosomes for proteolytic degradation, independent of initial which proceeds via Cbl-independent mechanisms. Disruption of Cbl function or ubiquitination sites results in receptor and sustained signaling, highlighting the importance of this process in terminating FGFR1 activity. Extrinsic inhibition is provided by modulators like SEF (similar expression to FGF), a secreted or membrane-bound protein that directly interacts with FGFR1 to block its activation. SEF binds to the extracellular domain of FGFR1, interfering with ligand-induced receptor dimerization and subsequent trans-autophosphorylation, thereby reducing tyrosine phosphorylation by over 70% and inhibiting downstream ERK activation. This mechanism acts upstream of Ras, offering an additional layer of regulation distinct from intracellular feedback loops.

Biological Roles

Embryonic Development

Fibroblast growth factor receptor 1 (FGFR1) plays a critical role in early embryonic development, particularly during induction and . In models, FGFR1-null embryos exhibit severe defects in mesodermal patterning, with an accumulation of undifferentiated cells at the and failure to properly migrate and differentiate into mesodermal lineages, leading to embryonic lethality by embryonic day 6.5 (E6.5). These findings indicate that FGFR1 transduces essential (FGF) signals required for specifying mesodermal cell fates and regional organization during . FGFR1 also contributes to in embryonic endothelial cells, primarily through signaling induced by FGF2, which promotes endothelial proliferation and vessel formation during early vascular development. Although global FGFR1 precludes direct assessment of endothelial-specific roles due to early , studies highlight FGF2-FGFR1 interactions as key for initiating angiogenic responses in developing vasculature. In embryonic contexts, this pathway supports the differentiation and migration of endothelial precursors to form the initial vascular network. In neural development, FGFR1 is essential for brain patterning and neural crest cell migration and differentiation, with expression in neural crest populations facilitating cranial neural crest-derived structures such as the and face. Similarly, FGFR1 mediates apical ectodermal (AER)-derived FGF signaling in the limb bud , driving proximal-distal outgrowth and patterning of the developing limb. Conditional FGFR1 inactivation reveals additional phenotypes, including impaired somitogenesis due to disrupted segmentation clock regulation and heart defects arising from abnormal cardiac specification and outflow tract development. Isoform specificity influences these processes, with certain FGFR1 variants predominant in embryonic neural and mesenchymal tissues. Recent studies using single-cell sequencing of embryos from 7 to 9 weeks confirm FGFR1 expression in fetal tissues, particularly in mesenchymal progenitor and clusters, where it participates in NCAM1-FGFR1 signaling to promote neuronal differentiation during early . These observations align with murine data, underscoring FGFR1's conserved role in embryonic patterning.

Adult Physiology and Homeostasis

In adult organisms, FGFR1 plays a pivotal role in by facilitating epithelial-mesenchymal interactions that promote tissue repair. Specifically, FGFR1 signaling in enhances and proliferation, essential for re-epithelialization at sites; conditional knockout of FGFR1 and FGFR2 in mouse delays closure, underscoring their necessity. This receptor also drives epithelial-mesenchymal transition (EMT) in -edge through FGF2 stimulation, upregulating transcription factors like SNAI2/Snail2 while downregulating E-cadherin, which accelerates healing by enabling mesenchymal-like motility without excessive under physiological conditions. In mesenchymal cells, FGFR1 supports fibroblast activation and remodeling, balancing repair to prevent pathological scarring. FGFR1 contributes to and via the FGF23-FGFR1-Klotho axis, where it acts as the primary receptor in renal and cells. FGF23, secreted by osteocytes, binds the FGFR1-Klotho complex to inhibit renal by downregulating NaPi-2a/2c transporters, thereby maintaining serum levels and preventing ectopic mineralization. In , FGFR1 deletion in adult mice elevates mass by boosting proliferation and modulating activity, illustrating its role in dynamic remodeling to sustain skeletal integrity. This axis also suppresses 1,25-dihydroxyvitamin D synthesis, fine-tuning calcium- balance for long-term health. In the adult brain, FGFR1 supports hippocampal neurogenesis and synaptic plasticity, linking progenitor proliferation to cognitive maintenance. Conditional FGFR1 knockout in neural progenitors impairs in the dentate gyrus, reducing new neuron integration and disrupting (LTP) at perforant path-granule cell synapses, as evidenced by diminished LTP induction in mutant mice. Environmental enrichment enhances this process by activating FGFR1 autonomously in neurogenic cells, expanding progenitor pools and bolstering synaptic strengthening for adaptive plasticity. These functions preserve hippocampal circuitry, aiding in mature brains. FGFR1 mediates metabolic in , particularly through insulin sensitization. In adipocytes, FGFR1 activation by FGF21, in complex with βKlotho, rapidly improves insulin sensitivity by enhancing and utilization, independent of initial ; for instance, FGFR1/βKlotho agonism increases glucose infusion rates by up to 152% in obese models within days. Adipose-specific FGFR1 knockout abolishes FGF21's effects on insulin lowering and elevation, confirming its central role in and glucose to counteract metabolic stress. Recent studies highlight FGFR1's involvement in aging-related vascular maintenance, particularly in endothelial cells where it sustains against age-induced stressors. Endothelial FGFR1 signaling prevents endothelial-to-mesenchymal transition (EndMT) and in response to inflammatory cues, preserving vascular integrity; its deficiency exacerbates vascular leakage and remodeling deficits in adult models. A 2025 review emphasizes FGFR1's bidirectional regulation of endothelial function, including attenuation of and phenotypic switching in vascular cells, which supports resilience in aging vasculature amid chronic low-grade .

Clinical Relevance

Congenital Disorders

Fibroblast growth factor receptor 1 (FGFR1) mutations underlie several congenital disorders, primarily through loss-of-function or gain-of-function mechanisms that disrupt developmental signaling during embryogenesis. These variants often exhibit autosomal dominant with variable and expressivity, leading to a spectrum of phenotypes ranging from isolated to severe craniofacial and limb malformations. Diagnostic criteria typically involve clinical evaluation of syndromic features combined with to confirm FGFR1 variants, while prevalence varies by disorder but remains low overall. Osteoglophonic dysplasia (OGD) is a rare skeletal dysplasia caused by heterozygous gain-of-function mutations in FGFR1, typically affecting the transmembrane or juxtamembrane domain (e.g., N330I, Y463C), leading to constitutive receptor activation and disrupted . It presents with rhizomelic , , prominent supraorbital ridges, depressed , metaphyseal , and nonossifying bone lesions that may predispose to fractures. Inheritance is autosomal dominant, often de novo, with full but variable expressivity; the disorder is extremely rare, with prevalence below 1 in 1,000,000 and fewer than 50 cases reported worldwide as of 2024. Diagnosis relies on radiographic findings and targeted FGFR1 sequencing. Kallmann syndrome (KS), or idiopathic hypogonadotropic hypogonadism type 2 (IHH2), is the most common congenital disorder linked to FGFR1, accounting for approximately 10% of cases. It results from heterozygous loss-of-function mutations, such as missense (e.g., R250Q, G237S), nonsense (e.g., R622X), frameshift (e.g., 1970delCA), and splice-site variants, which impair FGF signaling essential for (GnRH) neuron migration from the olfactory placode to the . Phenotypically, affected individuals present with , or , and variable features like cleft palate, dental agenesis, and bimanual synkinesia; incomplete is common, with asymptomatic carriers reported and oligogenic contributions from genes like FGF8 or PROKR2. The disorder has an estimated prevalence of 1 in 30,000 males and 1 in 120,000 females, with diagnosis relying on low serum gonadotropins, , olfactory testing, and sequencing of FGFR1 exons. Recent studies have identified novel variants, such as frameshifts in Chinese cohorts, underscoring ongoing genetic heterogeneity. Pfeiffer syndrome type 1, a disorder, arises from the recurrent gain-of-function P252R in the domain (TKD) of FGFR1, which enhances ligand binding affinity and constitutive receptor activation. This autosomal dominant variant leads to premature fusion of cranial sutures, resulting in turribrachycephaly, midface , and broad or deviated thumbs and great toes, with generally milder phenotypes compared to FGFR2-associated forms. shows full but variable expressivity, affecting skeletal development without or severe anomalies. The syndrome's overall is about 1 in 100,000 live births, with FGFR1 mutations comprising a subset; diagnosis is based on radiographic evidence of and targeted . Hartsfield syndrome, characterized by the triad of , , and cleft lip/palate, is caused by heterozygous or homozygous missense mutations in FGFR1, such as C725Y, L165S, and D623Y, often acting in a dominant-negative manner to disrupt midline patterning and limb bud formation. These variants show autosomal dominant inheritance with de novo occurrences common, and variable severity including and hypothalamic dysfunction. The disorder is extremely rare, with fewer than 40 cases reported and a prevalence below 1 in 1,000,000; diagnostic confirmation requires for , limb examination, and whole-exome sequencing. A novel variant was identified in a 2023 prenatal case, highlighting FGFR1 as the primary genetic cause.

Oncogenic Mechanisms and Cancer Associations

Aberrations in the FGFR1 , including amplifications, activating , and fusions, contribute to oncogenesis by constitutively activating downstream signaling pathways that promote , survival, and . FGFR1 amplification at the 8p11 locus is a common genetic alteration observed in various solid tumors, occurring in 9-22% of non-small cell lung cancers (NSCLC), particularly the squamous cell carcinoma subtype, where it drives tumor growth through ligand-independent receptor dimerization and enhanced activity. Similarly, FGFR1 amplification is present in 10-16% of estrogen receptor-positive (ER+) breast cancers, correlating with endocrine resistance and poorer prognosis due to sustained activation of the MAPK and PI3K/AKT pathways. In hematopoietic malignancies, fusions such as ZMYM2-FGFR1, resulting from chromosomal translocations at 8p11, characterize the 8p11 myeloproliferative syndrome, leading to ligand-independent oncogenic signaling and rapid progression to . Activating point mutations in FGFR1, such as N546K in the kinase domain, enhance receptor autophosphorylation and catalytic activity, resulting in constitutive signaling even in the absence of (FGF) ligands. This disrupts normal regulatory mechanisms, promoting uncontrolled cell proliferation and is recurrent in pediatric tumors. FGFR1 alterations are associated with diverse cancer types; in pediatric gliomas, they occur in approximately 8.9% of cases, with FGFR1 being one of the most frequently affected family members, driving low-grade gliomagenesis through diverse structural variants and point mutations as detailed in a 2025 genomic analysis. In , FGFR1 amplification defines a distinct aggressive subtype with 3.8% , marked by inferior disease-free independent of other prognostic factors, as identified in a large-scale 2025 profiling study. features FGFR1 overexpression that regulates E2F1-mediated transcription, sustaining progression via the EZH2-Rb axis, as shown in 2023 functional studies. Additionally, FGFR1 fusions, such as FOXO1-FGFR1, serve as novel drivers in , while FN1-FGFR1 fusions are frequent in phosphaturic mesenchymal tumors, contributing to tumor-induced through dysregulated FGF23 signaling. Oncogenic mechanisms of FGFR1 aberrations often involve the establishment of loops, where tumor cells produce FGF ligands that bind and activate FGFR1, fostering self-sustained growth and evasion of , particularly in NSCLC models. These alterations also confer resistance to standard therapies; for instance, FGFR1 amplification in promotes resistance to CDK4/6 inhibitors and endocrine treatments by maintaining proliferative signaling. Co-occurring mutations, such as those in TP53, exacerbate FGFR1-driven oncogenesis by impairing DNA damage responses and enhancing genomic instability, as observed in co-mutated pediatric gliomas where TP53 alterations modulate therapeutic vulnerabilities. Recent precision reviews indicate that FGFR1 alterations, including amplifications and mutations, are present in 5-15% of solid tumors across multiple histologies, underscoring their broad relevance in paradigms.

Therapeutic Targeting

FGFR1-Specific Inhibitors

FGFR1-specific inhibitors are small-molecule compounds designed to selectively target the domain of FGFR1, often extending to other FGFR isoforms, to disrupt aberrant signaling in diseases like cancer. These inhibitors primarily compete with ATP for binding in the kinase , with some employing covalent mechanisms to enhance potency and overcome resistance. Selectivity is crucial to minimize off-target effects on related kinases, such as VEGFR or other FGFRs, while achieving therapeutic efficacy in preclinical models. Pan-FGFR inhibitors, which target FGFR1 alongside FGFR2, FGFR3, and FGFR4, represent an early class of agents with broad activity. Erdafitinib, an ATP-competitive inhibitor, exhibits potent inhibition of FGFR1 with an of approximately 1.2 nM, demonstrating efficacy against FGFR-driven proliferation in cell lines. Similarly, pemigatinib potently inhibits FGFR1 with an of 0.4 nM, showing selective growth suppression in FGFR-activated tumor cells compared to wild-type lines. These compounds bind reversibly in the ATP-binding pocket, but their pan-specificity can lead to broader toxicities. Next-generation isoform-selective inhibitors aim to enhance specificity for FGFR1 and FGFR3 while sparing FGFR2 and FGFR4 to reduce adverse effects. TYRA-300, an oral selective inhibitor for FGFR1/3, is advancing in 2025 clinical trials for FGFR-altered solid tumors, including phase 2 studies initiated in 2025 for low-grade intermediate-risk non-muscle invasive (SURF302) and pediatric (BEACH301), offering improved and reduced off-target inhibition. Futibatinib, a covalent irreversible inhibitor, targets a conserved residue in the FGFR1 kinase domain, maintaining activity against mutations like V561M that confer resistance to non-covalent agents. This covalent binding mode enhances duration of inhibition and overcomes steric hindrance from mutations in the residue. Most FGFR1 inhibitors are ATP-competitive, occupying the hinge to block , though allosteric inhibitors that bind outside the are under exploration for greater selectivity. Resistance mutations, such as V561M in the FGFR1 position, reduce inhibitor potency by 20- to 30-fold across classes, shifting the binding equilibrium and necessitating covalent or next-generation designs. In preclinical studies, FGFR1 inhibitors induce significant tumor regression in FGFR1-amplified xenograft models, such as and lines, with doses achieving 50-80% reduction in tumor volume over 3-4 weeks. Common toxicity profiles include due to FGFR1-mediated regulation in and , observed in models at therapeutic doses. Advances in 2025 emphasize isoform-selective inhibitors like TYRA-300, which minimize off-target FGFR4 inhibition to mitigate toxicities such as and improve therapeutic windows in FGFR1-driven malignancies. These developments prioritize structural optimizations for FGFR1/3 specificity, showing enhanced preclinical efficacy without compromising antitumor activity.

Clinical Trials and Emerging Therapies

In 2024, the U.S. (FDA) granted full approval to erdafitinib (Balversa), a pan-FGFR inhibitor targeting FGFR1 among others, for adult patients with locally advanced or metastatic urothelial harboring susceptible FGFR3 alterations who have progressed following platinum-containing . Earlier on August 26, 2022, with ongoing relevance into 2025, the FDA approved pemigatinib (Pemazyre), a selective FGFR1-3 inhibitor, for relapsed or myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) rearrangement, including those associated with 8p11 myeloproliferative , a rare and aggressive blood cancer. These approvals highlight FGFR1-targeted therapies' role in precision medicine for genetically defined subsets of hematologic and solid malignancies. Clinical trials evaluating FGFR1 inhibitors have demonstrated promising yet variable efficacy across tumor types. In the phase 2 FOENIX-CCA2 trial for FGFR2-fusion-positive intrahepatic , futibatinib, an irreversible FGFR1-4 inhibitor, achieved a median (PFS) of 9.7 months in this single-arm study (historical PFS ~3-4 months), though FGFR1 alterations were less prevalent in this cohort. For non-small cell (NSCLC), particularly squamous with FGFR1 amplification, phase 2 trials of futibatinib and other FGFR inhibitors report objective response rates (ORR) of approximately 10-20%, with PFS around 3-5 months in biomarker-selected patients, underscoring the need for FGFR1-specific enrichment. In hormone receptor-positive resistant to endocrine , a 2025 co-clinical trial combined FGFR inhibition with CDK4/6 inhibitors and degraders, showing restored sensitivity in FGFR1/2-amplified models and preliminary ORR of 40% in early-phase data from patients with FGFR alterations. Outcomes in FGFR1-altered , where fusions and amplifications occur in approximately 1-5% of cases, include ORR of ~10-20% with inhibitors like pemigatinib and futibatinib, with durable responses in fusion-positive subsets but shorter durations in amplification-driven disease. Resistance frequently emerges via secondary on-target mutations, such as (V561M) or molecular brake alterations in the FGFR1 domain, leading to polyclonal escape clones and reduced inhibitor binding, as detailed in 2024 genomic analyses of post-treatment biopsies. Emerging therapies focus on combinations to overcome resistance and expand applicability. FGFR1 inhibition with pemigatinib has shown synergy with tumor-treating fields (TTFields) in stem cells harboring FGFR alterations, enhancing and reducing clonogenicity in preclinical 2025 studies, with phase 1/2 trials underway for recurrent gliomas. Antibody-drug conjugates (ADCs) targeting FGFR1, such as tetravalent antibody-maytansinoid constructs, demonstrate selective in FGFR1-overexpressing breast and cells by promoting receptor internalization and drug release, with early-phase trials exploring their use in amplification-positive solid tumors. A key challenge in FGFR1-targeted trials remains biomarker selection, where (FISH) detects amplifications with copy number thresholds >6-10, but next-generation sequencing (NGS) better identifies functional fusions and co-alterations, correlating with higher response rates (up to 40%) compared to FISH alone (8-11%). Future directions emphasize NGS-based companion diagnostics to refine patient stratification and monitor resistance.

Molecular Interactions

Interactions with FGF Ligands

Fibroblast growth factor receptor 1 (FGFR1) interacts with multiple members of the (FGF) family, primarily through its extracellular immunoglobulin-like domains, to initiate signaling cascades essential for cellular processes. Canonical paracrine FGF ligands bind FGFR1 with specificity influenced by of the receptor into IIIb (epithelial-preferred) and IIIc (mesenchymal-preferred) isoforms, as well as the presence of proteoglycans (HSPGs) as essential cofactors. Among canonical ligands, FGF1 exhibits ubiquitous binding affinity to both FGFR1-IIIb and FGFR1-IIIc isoforms, enabling broad across tissues due to its ability to interact with all FGFR variants. In contrast, FGF2, known for its angiogenic properties, preferentially binds FGFR1-IIIc with high affinity, while showing lower interaction with the IIIb isoform. FGF4 and FGF5, critical for embryonic patterning and limb development, also display strong selectivity for FGFR1-IIIc, with minimal engagement of IIIb, highlighting isoform-specific ligand-receptor matching that ensures tissue-appropriate signaling. HSPGs, such as syndecans and glypicans on cell surfaces, act as coreceptors by forming a ternary complex with FGF ligands and FGFR1, dramatically enhancing binding affinity by 10- to 100-fold through stabilization of the ligand-receptor dimer and promotion of higher-order oligomerization. This modulation is particularly pronounced for paracrine FGFs like FGF1 and FGF2, where HS chain sulfation and length (typically ≥8 saccharide units) dictate the efficiency of complex assembly, thereby restricting ligand diffusion and amplifying localized signaling gradients. Non-canonical endocrine FGFs, including FGF19, FGF21, and FGF23, engage FGFR1 primarily through the IIIc isoform, with FGF19 and FGF21 using β-Klotho as a coreceptor and FGF23 using α-Klotho, bypassing HSPG dependence to enable systemic hormonal actions such as metabolic regulation. For instance, FGF19 and FGF21 form stable complexes with FGFR1c–β-Klotho, facilitating glucose and homeostasis without the paracrine restriction imposed by HSPGs, whereas FGF23 signals via FGFR1c–α-Klotho for and regulation. In embryonic development, spatiotemporal FGF gradients, often involving FGF8 and near FGFR1-expressing cells, drive morphogenetic processes like induction and neural patterning by establishing threshold-dependent activation of FGFR1. Recent structural studies, including cryo-EM analyses of related ternary complexes, have revealed asymmetric arrangements in FGF-FGFR-HS interactions, providing insights into how ligand gradients translate to precise developmental outcomes, as exemplified by the FGF23–FGFR1c–αKlotho–HS quaternary complex resolved at near-atomic resolution. Pathologically, autocrine loops involving FGF2 and FGFR1 promote tumor progression in cancers such as non-small cell lung carcinoma and , where upregulated FGF2 secretion sustains self-stimulation of FGFR1, enhancing proliferation and survival independent of external ligands.

Interactions with Adaptor and Regulatory Proteins

Upon , FGFR1 recruits the adaptor proteins FRS2α and FRS2β to its juxtamembrane region through constitutive binding mediated by the phosphotyrosine-binding (PTB) domain of FRS2, independent of receptor . These adaptors become tyrosine-phosphorylated upon FGFR1 , enabling recruitment of the Grb2-SOS complex, which in turn activates the Ras/ERK signaling pathway by facilitating guanine nucleotide exchange on Ras. FRS2α primarily drives mitogenic signaling, while FRS2β modulates similar pathways with tissue-specific nuances, though both dock similarly to FGFR1. Phosphorylation of 766 (Y766) in the C-terminal tail of FGFR1 creates a docking site for the of Cγ (PLCγ), leading to its activation and subsequent hydrolysis of to generate inositol 1,4,5-trisphosphate and diacylglycerol, which mobilizes intracellular Ca²⁺ stores and activates . This PLCγ pathway operates in parallel to FRS2-mediated signaling and is essential for certain calcium-dependent responses. FGFR1 also interacts with the adaptor protein Crk (and its homolog CrkL), which binds to phosphorylated residues on the receptor or associated scaffolds like FRS2, recruiting the DOCK180 to activate Rac1 and promote cytoskeletal reorganization and cell shape changes. These interactions facilitate migratory and morphogenetic processes without directly impinging on canonical MAPK activation. Negative regulation of FGFR1 signaling involves inhibitory proteins such as SEF (Sprouty/Spred-related enhancer of FGFR signaling), which binds to the intracellular domain of FGFR1 and suppresses activity by inhibiting autophosphorylation, thereby attenuating downstream ERK activation upstream of Ras. SEF acts as a feedback inhibitor to fine-tune signaling duration and prevent excessive pathway activation. Protein tyrosine phosphatases, including SHP2 (), modulate FGFR1 signaling by dephosphorylating specific tyrosine residues on the receptor and its substrates, such as FRS2, to terminate or balance activation; SHP2's activity is partially required for sustained signaling but also contributes to events that limit prolonged ERK activation. Other like PTPRG further downregulate FGFR1 , accounting for a significant portion of basal in early signaling phases. Recent mass spectrometry-based interactome studies have identified additional FGFR1 binding partners, including novel nuclear envelope-associated proteins when the receptor is glycosylated, expanding the known regulatory network beyond classical adaptors. Protein-protein interaction (PPI) networks, as curated in the STRING database, reveal high-confidence associations of FGFR1 with FRS2α/β, PLCγ, Crk, SHP2, and SEF, with an enrichment p-value indicating non-random clustering (PPI enrichment p < 1.0e-16), underscoring a modular interactome that integrates positive and negative regulators for signaling fidelity.

References

  1. https://www.ncbi.nlm.nih.gov/gene/2260
  2. https://omim.org/entry/136350
  3. https://medlineplus.gov/genetics/gene/fgfr1/
  4. https://www.nature.com/articles/s41392-020-00222-7
  5. https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000077782
  6. https://www.ensembl.org/Homo_sapiens/Transcript/Summary?db=core;t=ENST00000447712
  7. https://pubmed.ncbi.nlm.nih.gov/11756440/
  8. https://www.nature.com/articles/s42003-024-06602-x
  9. https://ijdb.ehu.eus/article/pdf/12141425
  10. https://www.researchgate.net/publication/226774464_Evolutionarily_conserved_and_divergent_expression_of_members_of_the_FGF_receptor_family_among_vertebrate_embryos_as_revealed_by_FGFR_expression_patterns_in_Xenopus
  11. https://onlinelibrary.wiley.com/doi/10.1002/jcp.24649
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC3825415/
  13. https://www.jbc.org/article/S0021-9258%2819%2934544-2/pdf
  14. https://anatomypubs.onlinelibrary.wiley.com/doi/10.1002/dvdy.20441
  15. https://gtexportal.org/home/gene/FGFR1
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC6731303/
  17. https://www.science.org/doi/10.1126/sciadv.abi6648
  18. https://www.uniprot.org/uniprotkb/P11362/entry
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC6299260/
  20. https://www.rcsb.org/structure/1CVS
  21. https://www.sciencedirect.com/science/article/pii/S0092867400801312
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC6627960/
  23. https://elifesciences.org/articles/88144
  24. https://pubmed.ncbi.nlm.nih.gov/15096041/
  25. https://www.researchgate.net/publication/8607882_Kinetic_Model_for_FGF_FGFR_and_Proteoglycan_Signal_Transduction_Complex_Assembly
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC2080618/
  27. https://www.sciencedirect.com/science/article/pii/S1097276500000733
  28. https://www.sciencedirect.com/science/article/pii/S0092867400800513
  29. https://www.pnas.org/doi/10.1073/pnas.0914157107
  30. https://www.nature.com/articles/s41586-023-06155-9
  31. https://www.nature.com/articles/ncomms10262
  32. https://www.sciencedirect.com/science/article/pii/S109727650600044X
  33. https://pubmed.ncbi.nlm.nih.gov/8622701/
  34. https://www.nature.com/articles/ncomms8877
  35. https://genesdev.cshlp.org/content/38/9-10/393.full
  36. https://pubmed.ncbi.nlm.nih.gov/12402043/
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC11159094/
  38. https://pubmed.ncbi.nlm.nih.gov/23405013/
  39. https://www.researchgate.net/publication/235605227_ERK-Mediated_Phosphorylation_of_Fibroblast_Growth_Factor_Receptor_1_on_Ser777_Inhibits_Signaling
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC2488279/
  41. https://pubmed.ncbi.nlm.nih.gov/12604616/
  42. https://www.sciencedirect.com/science/article/pii/S002192581964559X
  43. https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-024-01302-9
  44. https://pubmed.ncbi.nlm.nih.gov/22992463/
  45. https://doi.org/10.1038/s41598-020-75584-7
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC8622657/
  47. https://doi.org/10.1152/ajprenal.90742.2008
  48. https://www.nature.com/articles/boneres20143
  49. https://doi.org/10.1038/nature05315
  50. https://pubmed.ncbi.nlm.nih.gov/17239352/
  51. https://www.jneurosci.org/content/41/13/2899
  52. https://doi.org/10.1016/j.ebiom.2015.05.028
  53. https://doi.org/10.1016/j.molmet.2012.08.007
  54. https://doi.org/10.1016/j.bcp.2025.117511
  55. https://www.omim.org/entry/136350
  56. https://pubmed.ncbi.nlm.nih.gov/12627230/
  57. https://medlineplus.gov/genetics/condition/osteoglophonic-dysplasia/
  58. https://www.ncbi.nlm.nih.gov/books/NBK602944/
  59. https://omim.org/entry/166250
  60. https://medlineplus.gov/genetics/condition/kallmann-syndrome/
  61. https://www.pnas.org/doi/10.1073/pnas.0600962103
  62. https://pubmed.ncbi.nlm.nih.gov/36859276/
  63. https://pubmed.ncbi.nlm.nih.gov/7874169/
  64. https://www.ncbi.nlm.nih.gov/books/NBK532882/
  65. https://rarediseases.org/rare-diseases/pfeiffer-syndrome/
  66. https://pubmed.ncbi.nlm.nih.gov/23812909/
  67. https://www.omim.org/entry/615465
  68. https://pubmed.ncbi.nlm.nih.gov/38013637/
  69. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.780650/full
  70. https://aacrjournals.org/clincancerres/article/25/21/6443/265564/FGFR1-Amplification-Mediates-Endocrine-Resistance
  71. https://pubmed.ncbi.nlm.nih.gov/23751892/
  72. https://pmc.ncbi.nlm.nih.gov/articles/PMC9052553/
  73. https://www.nature.com/articles/s41467-025-61820-z
  74. https://www.esmoopen.com/article/S2059-7029%2825%2901430-9/fulltext
  75. https://www.nature.com/articles/s41375-023-02006-8
  76. https://onlinelibrary.wiley.com/doi/full/10.1002/gcc.23232
  77. https://www.sciencedirect.com/science/article/pii/S0893395222015216
  78. https://aacrjournals.org/clincancerres/article/17/15/5016/76450/Fibroblast-Growth-Factor-Receptors-Are-Components
  79. https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01558-1
  80. https://www.sciencedirect.com/science/article/pii/S2352396415000572
  81. https://www.sciencedirect.com/science/article/abs/pii/S1043661819326398
  82. https://www.sciencedirect.com/science/article/pii/S1040842824002075
  83. https://ir.tyra.bio/news-releases/news-release-details/tyra-biosciences-doses-first-patient-phase-2-study-tyra-300-low
  84. https://ir.tyra.bio/news-releases/news-release-details/tyra-biosciences-announces-first-child-dosed-beach301-its-phase
  85. https://www.sciencedirect.com/science/article/pii/S0165614725002202
  86. https://www.nature.com/articles/s42004-021-00623-x
  87. https://www.sciencedirect.com/science/article/pii/S1084952115001664
  88. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-erdafitinib-locally-advanced-or-metastatic-urothelial-carcinoma
  89. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pemigatinib-relapsed-or-refractory-myeloidlymphoid-neoplasms-fgfr1-rearrangement
  90. https://www.nejm.org/doi/full/10.1056/NEJMoa2206834
  91. https://www.nature.com/articles/s41698-025-01106-1
  92. https://www.annalsofoncology.org/article/S0923-7534%2824%2904976-7/fulltext
  93. https://www.nature.com/articles/s41420-025-02542-5
  94. https://molmed.biomedcentral.com/articles/10.1186/s10020-021-00306-2
  95. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02167-9
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC4393358/
  97. https://pmc.ncbi.nlm.nih.gov/articles/PMC4906438/
  98. https://www.oncotarget.com/article/9515/text/
  99. https://pmc.ncbi.nlm.nih.gov/articles/PMC85215/
  100. https://febs.onlinelibrary.wiley.com/doi/10.1016/j.febslet.2009.01.042
  101. https://pmc.ncbi.nlm.nih.gov/articles/PMC317047/
  102. https://pmc.ncbi.nlm.nih.gov/articles/PMC4323088/
  103. https://pmc.ncbi.nlm.nih.gov/articles/PMC5818251/
  104. https://genesdev.cshlp.org/content/29/17/1863.full.pdf
  105. https://rupress.org/jcb/article/171/4/663/52024/Pleiotropic-effects-of-FGFR1-on-cell-proliferation
  106. https://pmc.ncbi.nlm.nih.gov/articles/PMC108981/
  107. https://www.mdpi.com/2073-4409/10/6/1342
  108. https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01203-3
  109. https://string-db.org/network/9606/ENSP00000393312
Add your contribution
Related Hubs
User Avatar
No comments yet.