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Proto-oncogene tyrosine-protein kinase Src
Proto-oncogene tyrosine-protein kinase Src
Proto-oncogene tyrosine-protein kinase Src
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This article is about the kinase c-Src, for the kinase that phosphorylates c-Src, see CSK.
SRC
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSRC, ASV, SRC1, c-p60-Src, SRC proto-oncogene, non-receptor tyrosine kinase, THC6
External IDsOMIM: 190090; MGI: 98397; HomoloGene: 21120; GeneCards: SRC; OMA:SRC - orthologs
EC number2.7.10.2
Orthologs
SpeciesHumanMouse
Entrez

6714

20779

Ensembl

ENSG00000197122

ENSMUSG00000027646

UniProt

P12931

P05480

RefSeq (mRNA)

NM_005417
NM_198291

NM_001025395
NM_009271

RefSeq (protein)

NP_005408
NP_938033

NP_001020566
NP_033297

Location (UCSC)Chr 20: 37.34 – 37.41 MbChr 2: 157.42 – 157.47 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, or simply c-Src (cellular Src; pronounced "sarc", as it is short for sarcoma), is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. It belongs to a family of Src family kinases and is similar to the v-Src (viral Src) gene of Rous sarcoma virus. It includes an SH2 domain, an SH3 domain and a tyrosine kinase domain. Two transcript variants encoding the same protein have been found for this gene.[5]

c-Src phosphorylates specific tyrosine residues in other tyrosine kinases. It plays a role in the regulation of embryonic development and cell growth. An elevated level of activity of c-Src is suggested to be linked to cancer progression by promoting other signals.[6] Mutations in c-Src could be involved in the malignant progression of colon cancer. c-Src should not be confused with CSK (C-terminal Src kinase), an enzyme that phosphorylates c-Src at its C-terminus and provides negative regulation of Src's enzymatic activity.

c-Src was originally discovered by American scientists J. Michael Bishop and Harold E. Varmus, for which they were awarded the 1989 Nobel Prize in Physiology or Medicine.[7]

Discovery

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In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens possess a gene that is structurally closely related to v-Src.[8] The normal cellular gene was called c-src (cellular-src).[9] This discovery changed the current thinking about cancer from a model wherein cancer is caused by a foreign substance (a viral gene) to one where a gene that is normally present in the cell can cause cancer. It is believed that at one point an ancestral virus mistakenly incorporated the c-Src gene of its cellular host. Eventually this normal gene mutated into an abnormally functioning oncogene within the Rous sarcoma virus. Once the oncogene is transfected back into a chicken, it can lead to cancer.

Structure

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There are 9 members of the Src family kinases: c-Src, Yes, Fyn, Fgr, Yrk, Lyn, Blk, Hck, and Lck.[10] The expression of these Src family members are not the same throughout all tissues and cell types. Src, Fyn and Yes are expressed ubiquitously in all cell types while the others are generally found in hematopoietic cells.[11][12][13][14]

c-Src is made up of 6 functional regions: Src homology 4 domain (SH4 domain), unique region, SH3 domain, SH2 domain, catalytic domain and short regulatory tail.[15] When Src is inactive, the phosphorylated tyrosine group at the 527 position interacts with the SH2 domain which helps the SH3 domain interact with the flexible linker domain and thereby keeps the inactive unit tightly bound. The activation of c-Src causes the dephosphorylation of the tyrosine 527. This induces long-range allostery via protein domain dynamics, causing the structure to be destabilized, resulting in the opening up of the SH3, SH2 and kinase domains and the autophosphorylation of the residue tyrosine 416.[16][17][18]

c-Src can be activated by many transmembrane proteins that include: adhesion receptors, receptor tyrosine kinases, G-protein coupled receptors and cytokine receptors. Most studies have looked at the receptor tyrosine kinases and examples of these are platelet derived growth factor receptor (PDGFR) pathway and epidermal growth factor receptor (EGFR).

Src contains at least three flexible protein domains, which, in conjunction with myristoylation, can mediate attachment to membranes and determine subcellular localization.[19]

Function

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This proto-oncogene may play a role in the regulation of embryonic development and cell growth.

When src is activated, it promotes survival, angiogenesis, proliferation and invasion pathways. It also regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion,[20][21] and regulates matrix metalloproteinase-9 activity after intracerebral hemorrhage.[22]

Role in cancer

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The activation of the c-Src pathway has been observed in about 50% of tumors from colon, liver, lung, breast and the pancreas.[23] Since the activation of c-Src leads to the promotion of survival, angiogenesis, proliferation and invasion pathways, the aberrant growth of tumors in cancers is observed. A common mechanism is that there are genetic mutations that result in the increased activity or the overexpression of the c-Src leading to the constant activation of the c-Src.

Colon cancer

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The activity of c-Src has been best characterized in colon cancer. Researchers have shown that Src expression is 5 to 8 fold higher in premalignant polyps than normal mucosa.[24][25][26] The elevated c-Src levels have also been shown to have a correlation with advanced stages of the tumor, size of tumor, and metastatic potential of tumors.[27][28]

Breast cancer

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EGFR activates c-Src while EGF also increases the activity of c-Src. In addition, overexpression of c-Src increases the response of EGFR-mediated processes. So both EGFR and c-Src enhance the effects of one another. Elevated expression levels of c-Src were found in human breast cancer tissues compared to normal tissues.[29][30][31]

Overexpression of Human Epidermal Growth Factor Receptor 2 (HER2), also known as erbB2, is correlated with a worse prognosis for breast cancer.[32][33] Thus, c-Src plays a key role in the tumor progression of breast cancers.

Prostate cancer

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Members of the Src family kinases Src, Lyn and Fgr are highly expressed in malignant prostate cells compared to normal prostate cells.[34] When the primary prostate cells are treated with KRX-123, which is an inhibitor of Lyn, the cells in vitro were reduced in proliferation, migration and invasive potential.[35] So the use of a tyrosine kinase inhibitor is a possible way of reducing the progression of prostate cancers.

As a drug target

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A number of tyrosine kinase inhibitors that target c-Src tyrosine kinase (as well as related tyrosine kinases) have been developed for therapeutic use.[36] One notable example is dasatinib which has been approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (PH+) acute lymphocytic leukemia (ALL).[37] Dasatinib is also in clinical trials for the use in non-Hodgkin’s lymphoma, metastatic breast cancer and prostate cancer. Other tyrosine kinase inhibitor drugs that are in clinical trials include bosutinib,[38] bafetinib, Saracatinib(AZD-0530), XLl-999, KX01 and XL228.[6] HSP90 inhibitor NVP-BEP800 has been described to affect stability of Src tyrosine kinase and growth of T-cell and B-cell acute lymphoblastic leukemias. [39]

Interactions

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Src (gene) has been shown to interact with the following signaling pathways:

Survival

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Angiogenesis

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Proliferation

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Motility

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Additional images

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Overview of signal transduction pathways involved in apoptosis.
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Top row:    Beta-strand region

   Hydrogen bonded turn    Helical region

site 2 2 lipid-binding
site 17 17 Phosphoserine
site 35 35 Phosphoserine
site 69 69 Phosphoserine
site 74 74 Phosphothreonine
site 75 75 Phosphoserine; by CDK5
region 87 93 Beta-strand region
region 88 143 SH3
site 88 88 swapped dimer interface [polypeptide binding]
site 93 93 peptide ligand binding site [polypeptide binding]
region 99 102 Beta-strand region
region 110 114 Beta-strand region
region 117 117 Splicing variant
region 118 126 Beta-strand region
region 127 129 Hydrogen bonded turn
region 132 136 Beta-strand region
region 137 139 Helical region
region 140 142 Beta-strand region
region 146 148 Helical region
region 147 247 SH2
region 152 154 Beta-strand region
site 158 158 autoinhibitory site [polypeptide binding]
site 158 158 phosphotyrosine binding pocket [polypeptide binding]
region 158 165 Helical region
region 167 170 Beta-strand region
region 174 179 Beta-strand region
region 176 176 Variant
region 181 183 Beta-strand region
region 187 195 Beta-strand region
site 187 187 Phosphotyrosine (By similarity)
region 196 198 Hydrogen bonded turn
region 199 209 Beta-strand region
site 205 205 hydrophobic binding pocket [polypeptide binding]
region 211 213 Beta-strand region
region 215 218 Beta-strand region
region 221 225 Beta-strand region
region 226 233 Helical region
region 237 237 Variant
region 240 242 Beta-strand region
region 256 259 Beta-strand region
region 267 269 Helical region
region 270 519 Tyrosine kinase
region 270 278 Beta-strand region
site 276 276 Active site (ATP binding)
region 283 289 Beta-strand region
site 290 290 SH3/SH2 domain interface [polypeptide binding]
region 290 292 Hydrogen bonded turn
region 293 299 Beta-strand region
site 298 298 ATP
region 302 304 Hydrogen bonded turn
region 307 319 Helical region
region 328 332 Beta-strand region
region 334 336 Beta-strand region
region 338 341 Beta-strand region
region 349 353 Helical region
region 355 358 Helical region
region 363 382 Helical region
site 389 389 Proton acceptor
region 392 394 Helical region
region 395 397 Beta-strand region
region 399 401 Helical region
region 403 405 Beta-strand region
site 406 406 activation loop (A-loop)
region 410 413 Helical region
region 417 420 Helical region
site 419 419 Phosphotyrosine; by autocatalysis; alternate
site 419 419 Phosphotyrosine; by FAK2; alternate (By similarity)
region 423 426 Hydrogen bonded turn
region 429 431 Helical region
region 434 439 Helical region
site 439 439 Phosphotyrosine
region 444 459 Helical region
region 460 462 Hydrogen bonded turn
region 471 479 Helical region
region 492 501 Helical region
site 501 501 S-nitrosocysteine (By similarity)
region 506 508 Helical region
site 511 511 Phosphothreonine
region 512 520 Helical region
region 521 523 Hydrogen bonded turn
site 522 522 Phosphotyrosine
site 530 530 Phosphotyrosine; by CSK

References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Proto-oncogene tyrosine-protein kinase Src

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from Grokipedia
Proto-oncogene tyrosine-protein kinase Src, commonly abbreviated as c-Src and encoded by the SRC gene (Gene ID: 6714) on human chromosome 20q11.23, is a 536-amino-acid that serves as the founding member of the Src family kinases (SFKs). This ubiquitously expressed protein plays essential roles in cellular signaling by phosphorylating residues on substrates, thereby regulating key processes including , differentiation, , , , and . The discovery of Src traces back to 1911, when Peyton Rous identified the (RSV) as a causative agent of sarcomas in chickens, with the viral oncogene v-Src later characterized as a in 1978. In 1976, J. Michael Bishop and demonstrated that v-Src has a cellular counterpart, c-Src, establishing it as a proto-oncogene capable of oncogenic transformation when deregulated, a breakthrough that earned them the 1989 Nobel Prize in Physiology or Medicine. Unlike its constitutively active viral form, cellular c-Src is tightly regulated to maintain physiological functions but becomes overexpressed or hyperactivated in various human cancers, contributing to hallmarks such as uncontrolled growth, invasion, metastasis, and metabolic reprogramming. Structurally, c-Src consists of several modular domains: an N-terminal SH4 domain for myristoylation and membrane anchoring, a unique domain specific to each SFK member, an SH3 domain that binds proline-rich sequences, an that recognizes phosphotyrosine motifs, a (SH1) domain responsible for catalytic activity, and a C-terminal regulatory tyrosine residue (Tyr527 in humans). In its inactive state, intramolecular interactions between SH2/SH3 domains and the phosphorylated Tyr527 (mediated by C-terminal Src , CSK) clamp the protein into a closed conformation, inhibiting autophosphorylation at the activating Tyr419 site within the kinase domain. Activation occurs through dephosphorylation of Tyr527 by protein tyrosine phosphatases (e.g., PTPRA) and disruption of autoinhibitory interactions in response to upstream signals from , receptors, or G-protein-coupled receptors, leading to autophosphorylation at Tyr419 and full activity. Beyond normal , deregulated Src activity is implicated in multiple pathologies, including (OMIM: 114500) and thrombocytopenia 6 (OMIM: 616937), where it drives aberrant signaling through pathways like FAK-mediated adhesion, PI3K/AKT survival, and transcription. In cancer, Src enhances metabolic flexibility by promoting via GLUT transporters, glycolytic flux through enzymes like and PFKFB3, and mitochondrial bioenergetics, thereby supporting tumor progression and therapeutic resistance. Its central role in integrating extracellular cues with intracellular responses underscores Src as a pivotal therapeutic target, with inhibitors like exploiting its deregulation for anticancer strategies.

History and Discovery

Initial Identification

The proto-oncogene tyrosine-protein kinase Src was first identified through investigations into the (RSV), a that induces tumors in chickens. In 1977, Joan S. Brugge and Ray L. Erikson at the reported the detection of a 60 kDa , designated pp60src, as the product of the viral v-src, using with antisera from RSV-tumor-bearing animals. This protein was transformation-specific, present in RSV-infected cells but absent in uninfected controls, marking the initial biochemical characterization of a viral oncogene product. Subsequent studies by Erikson's group demonstrated that pp60src possessed activity. In 1978, Mark S. Collett and Erikson showed that this activity was intrinsic to pp60src, as immune complexes containing the protein catalyzed the of added substrates, including autophosphorylation of pp60src itself. Further analysis in 1980 by Collett, Anthony F. Purchio, and Erikson established that the kinase specifically phosphorylated residues, distinguishing it from previously known serine/ kinases and identifying the first -specific . These early assays, involving 32P-labeled ATP and for phosphoamino acid analysis, confirmed the enzymatic mechanism underlying v-Src's transforming potential. The cellular homolog, c-Src, was identified in the mid-1970s through molecular hybridization experiments. In 1976, Dominique Stehelin, Harold E. Varmus, J. Michael Bishop, and Peter K. Vogt detected DNA sequences homologous to v-src in normal avian cells, indicating that the viral oncogene derived from a proto-oncogene in the host genome. Building on this, Bishop and Varmus's group cloned and partially sequenced the chicken c-src gene in 1981, revealing its structural similarity to v-src while noting differences that likely render the cellular version non-transforming under normal conditions. Their pioneering work on the cellular origins of retroviral oncogenes, exemplified by src, earned Bishop and Varmus the 1989 Nobel Prize in Physiology or Medicine.

Key Research Milestones

In the 1990s, significant progress was made in elucidating the structural basis of Src regulation through crystallographic studies. The three-dimensional structure of the c-Src domain was determined in 1997, revealing its bilobal architecture with key regulatory elements including the SH3 and SH2 domains that impose autoinhibition in the inactive state. Concurrently, the of the related Hck provided insights into conserved regulatory mechanisms across the family, highlighting the role of intramolecular interactions in kinase suppression. During the 2000s, research expanded on the Src family kinases (SFKs), identifying their distinct tissue-specific expression patterns that underpin specialized cellular functions. For instance, studies demonstrated differential expression of SFK members like Src, , and Lyn in hematopoietic versus non-hematopoietic tissues, correlating with roles in immune signaling and cytoskeletal dynamics. This period also saw the development and application of the first selective Src inhibitors, such as PP1 and PP2, which potently targeted SFKs with nanomolar affinity while sparing other kinases, enabling precise dissection of Src-dependent pathways in cellular models. The 2010s brought advances in visualizing Src's dynamic roles in cellular structures through live-cell imaging techniques. High-resolution imaging revealed Src's activation and recruitment to focal adhesions, where it orchestrates integrin-mediated signaling and essential for . Similarly, live imaging studies illuminated Src's involvement in podosome formation and turnover, showing its coordination with adaptor proteins like Tks5 to drive invasive protrusions in motile cells. Additionally, investigations uncovered non-canonical nuclear localization of Src, where it phosphorylates nuclear substrates to influence and DNA damage responses, expanding its regulatory scope beyond cytoplasmic signaling. From 2020 to 2025, computational approaches like simulations provided atomic-level insights into Src's conformational dynamics. Replica-exchange simulations of full-length Src in 2024 elucidated the equilibria at key residues Tyr419 and Tyr530 ( numbering), demonstrating how dual stabilizes intermediate states that fine-tune activity and autoinhibitory release. Parallel work established lipid-driven self-association models for Src, revealing that membrane phospholipids promote oligomerization via a conserved lysine cluster in the SH4 domain, thereby linking plasma membrane localization to enhanced autophosphorylation and signaling efficiency.

Molecular Structure and Regulation

Domain Organization

The proto-oncogene tyrosine-protein kinase Src consists of 536 amino acids and has a molecular mass of approximately 60 kDa. Its N-terminus features a myristoylation site at glycine residue 2, which promotes membrane association, along with palmitoylation at cysteine residue 3 for enhanced lipid raft targeting. From the N- to C-terminus, Src exhibits a modular domain architecture conserved among Src family kinases (SFKs). The SH4 domain encompasses the myristoylation and palmitoylation sites (residues 1–16), followed by the unique domain (residues 17–80), which is regulatory and shows sequence variability across SFKs. The SH3 domain (residues 81–142) adopts a β-sandwich fold for binding proline-rich motifs, while the SH2 domain (residues 148–245) contains a phosphotyrosine-binding pocket flanked by a central β-sheet and α-helices. A flexible linker region (residues 246–266) connects the SH2 domain to the bilobal kinase domain (residues 267–520), which features an N-terminal lobe with a β-sheet and helix C for ATP binding, and a larger C-terminal lobe dominated by α-helices. The structure concludes with a short C-terminal regulatory tail (residues 521–536) that includes the key tyrosine residue 530. The of the Src SH3-SH2- fragment, determined in 1997 at 1.5 resolution (PDB ID: 1FMK), reveals a compact inactive conformation in which the SH3 and SH2 domains assemble on the backside of the domain, occluding the . More recent full-length models derived from 2024 simulations confirm this compact arrangement in the inactive state, with the intrinsically disordered SH4-unique region (residues 1–83) folding back to interact with the SH3 and domains. Src displays approximately 60% amino acid sequence identity in its domain with other SFKs, such as Yes and , underscoring the conserved catalytic core across the family.

Activation and Inhibition Mechanisms

The inactive state of proto-oncogene tyrosine-protein Src is characterized by an autoinhibited conformation maintained through intramolecular clamping of its regulatory domains. The Src homology 3 (SH3) domain binds to a polyproline type II helix within the linker region connecting the SH2 and domains, while the Src homology 2 ( engages the phosphorylated at position 530 (pY530) in the C-terminal tail. This pY530 is primarily catalyzed by C-terminal Src (Csk), which docks onto Src via its own SH2 and SH3 domains to enforce the inhibitory interaction, thereby preventing substrate access to the and stabilizing a closed, low-activity . Activation of Src proceeds via coordinated dephosphorylation and phosphorylation events that disrupt this clamped conformation. Protein tyrosine phosphatases, such as PTP1B, dephosphorylate the inhibitory pY530, releasing the from the C-terminal tail and allowing the to disengage from the linker helix; this process is often triggered by upstream signals like . Concurrently, 419 (Y419) in the kinase domain's loop becomes phosphorylated, either through intramolecular autophosphorylation by Src or intermolecularly by like Abl, which aligns key catalytic residues and opens the cleft for ATP and substrate binding. These changes collectively transition Src to an open, catalytically competent state, with the released SH3 and SH2 domains available for downstream interactions. The catalytic activity of activated Src adheres to Michaelis-Menten kinetics, simplified for ATP as the variable substrate: v=kcat[Src][ATP]Km+[ATP]v = \frac{k_{\mathrm{cat}} [\mathrm{Src}] [\mathrm{ATP}]}{K_m + [\mathrm{ATP}]} where kcatk_{\mathrm{cat}} represents the , approximately 3 s−1^{-1} for wild-type active c-Src under standard assay conditions, reflecting its efficient phosphotransfer rate once derepressed. Src activity is also subject to allosteric inhibition, primarily through ATP-competitive inhibitors that bind the conserved cleft and mimic ATP to lock the in an inactive pose, often stabilizing the closed SH2-pY530 interaction. Recent insights highlight how lipid environments at the plasma membrane can induce Src dimerization via electrostatic interactions involving clusters in the N-terminal SH4 domain, thereby enhancing activation by facilitating trans-phosphorylation between monomers and bypassing some autoinhibitory constraints.

Physiological Functions

Role in Cell Signaling Pathways

Src plays a central role in integrating signals from receptor kinases (RTKs), such as the (EGFR) and platelet-derived growth factor receptor (PDGFR), in normal cellular responses. Upon binding, Src phosphorylates specific residues on these RTKs, enhancing their and facilitating the recruitment of adaptor proteins like and Shc. This phosphorylation event propagates the signal downstream to the (MAPK)/extracellular signal-regulated kinase (ERK) pathway, promoting changes that drive and differentiation in physiological contexts, such as tissue repair and . In adhesion signaling, Src localizes to s where it interacts with and phosphorylates focal adhesion kinase (FAK) at key sites, including 397 (Y397) for Src binding and Y576 in the loop to boost FAK kinase activity. This FAK-Src complex further phosphorylates paxillin on residues, such as Y31 and Y118, which serve as docking sites for additional signaling molecules. These modifications promote dynamic remodeling of the actin cytoskeleton, enabling cell spreading, migration, and maintenance of tissue integrity during normal processes like . Src also mediates crosstalk between and G-protein-coupled receptors (GPCRs), amplifying extracellular cues into intracellular responses. Activation of β-integrins by components or GPCRs like the receptor recruits and activates Src, which in turn modulates Rho family (e.g., RhoA and Rac1) through of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs). This regulation facilitates and , supporting cytoskeletal reorganization essential for cell motility and shape changes in healthy tissues. Overall, Src amplifies growth factor and adhesion signals, with its kinase activity increasing up to several-fold upon stimulation, as measured by enhanced phospho-tyrosine levels in immunoblotting assays, thereby fine-tuning the intensity and duration of these pathways for balanced cellular function.

Involvement in Development and Tissue Homeostasis

Src plays a critical role in embryonic development, as evidenced by studies on knockout models. Mice lacking Src are viable but exhibit reduced size and osteopetrosis due to defects in osteoclast function and impaired bone resorption, leading to difficulties in tooth eruption that hinder feeding. These defects highlight Src's essential involvement in skeletal development during late embryogenesis. Additionally, Src contributes to neural tube closure by facilitating neural crest cell migration through the Src-Tks5 signaling pathway, which is vital for proper neural tube morphogenesis and preventing developmental anomalies. In angiogenesis, Src is selectively required for vascular endothelial growth factor (VEGF)-induced endothelial cell survival and vessel sprouting during embryonic vascularization, ensuring proper tissue perfusion. In bone , Src regulates osteoclast podosome formation and organization, which are actin-rich structures necessary for matrix degradation and . Src activity controls the dynamics of podosome and sealing zone formation, maintaining osteoclast polarity and efficient breakdown. Inhibition or absence of Src disrupts these processes, resulting in characterized by increased due to failed resorption. This underscores Src's balanced role in coordinating to support tissue integrity throughout life. Src also participates in immune response regulation, particularly through Src family kinases (SFKs) like Lck, which mediate T-cell activation by phosphorylating key substrates upon T-cell receptor engagement, thereby initiating downstream signaling for immune cell proliferation and differentiation. In B-cell signaling, Src family members, including c-Src, facilitate antigen receptor-induced tyrosine phosphorylation events that drive B-cell activation and antibody production. Furthermore, Src maintains epithelial barrier integrity by modulating E-cadherin interactions and tight junction stability, preventing paracellular leakage and supporting tissue compartmentalization in mucosal and endothelial layers. A recent discovery in 2025 revealed that Src isoforms, particularly N1-Src, regulate mRNA splicing during neural differentiation by phosphorylating RNA-binding proteins (RBPs) such as hnRNP A1 and Tra2α, which influences events critical for neuronal maturation and programs. This phosphorylation modulates RBP binding to splice sites, coordinating essential for neural development and .

Pathological Roles in Cancer

Oncogenic Mechanisms

The oncogenic transformation mediated by Src primarily arises from genetic and epigenetic alterations that disrupt its autoinhibitory mechanisms, leading to constitutive activity. Activating point in the SH2 or SH3 domains, such as the P344A substitution identified in a subset of advanced human colon cancers, abrogate intramolecular interactions and promote persistent activation. Similarly, v-Src-like C-terminal deletions that remove the inhibitory residue Tyr527 in human c-Src eliminate phosphorylation-dependent repression, resulting in unregulated function akin to the viral oncoprotein. of SRC, though less common than overexpression, has been documented in various solid tumors, contributing to elevated protein levels and enhanced signaling. Upstream dysregulation further amplifies Src activity through indirect mechanisms. Hyperactivity of receptor tyrosine s (RTKs), such as HER2 overexpression in , recruits and activates Src via direct binding or secondary messengers, bypassing normal regulatory thresholds. Loss or downregulation of the C-terminal Src (Csk), which phosphorylates Tyr527 to maintain autoinhibition, leads to unchecked Src and , as observed in and colon cancers where reduced Csk expression correlates with tumor progression. These alterations collectively shift Src from a transiently activated proto-oncogene to a persistently oncogenic driver. Downstream, hyperactive Src phosphorylates key substrates to foster cancer hallmarks. Phosphorylation of STAT3 at Y705 enhances its dimerization and nuclear translocation, driving transcription of genes that promote cell survival and proliferation. Similarly, Src-mediated tyrosine phosphorylation of β-catenin disrupts its degradation complex, stabilizing it for nuclear accumulation and activation of Wnt target genes that induce epithelial-mesenchymal transition (EMT) and metastatic potential. These effects culminate in enhanced survival signaling and motility.

Implications in Specific Cancers

In colon cancer, elevated Src activity is observed in approximately 80% of tumor tissues and strongly correlates with metastatic potential, as higher levels are associated with advanced Dukes staging and involvement. Hypophosphorylation of the inhibitory residue Tyr527, leading to Src , occurs frequently in colorectal tumors and enhances Wnt/β-catenin signaling by promoting β-catenin stabilization and nuclear translocation, thereby driving epithelial-mesenchymal transition and invasion. In , Src is particularly implicated in HER2-positive subtypes, where it interacts with HER2 to amplify downstream signaling that fosters tumor aggressiveness. The Src-FAK axis plays a central role in driving cell invasion, as Src phosphorylates FAK to reorganize the actin cytoskeleton and focal adhesions, facilitating degradation in HER2-overexpressing cells. Elevated Src levels are detected in a substantial proportion of invasive ductal carcinomas, contributing to progression from to metastatic disease. In , Src facilitates androgen-independent progression through direct interaction with the (AR), where Src-mediated tyrosine phosphorylation of AR enhances its transcriptional activity even in low-androgen environments, promoting cell survival and proliferation. Preclinical models demonstrate that Src inhibitors, such as , suppress AR signaling and reduce (PSA) secretion in androgen-refractory cell lines and xenografts, indicating potential to halt castration-resistant growth. In , SRC expression at invasive borders correlates with enhanced epithelial to mesenchymal transition (EMT) and poor prognosis. Beyond these cancers, Src contributes to progression by remodeling ; activated Src increases cytosolic production via of metabolic enzymes like ACLY, supporting lipid biosynthesis essential for tumor growth and survival. In a pan-cancer analysis, SRC expression correlates with immune cell infiltration in various tumor types, suggesting Src modulates the to influence prognosis.

Roles in Non-Cancer Diseases

Cardiovascular and Inflammatory Disorders

Src family kinases (SFKs), including Src, play a critical role in platelet by mediating signaling downstream of the receptor VI (GPVI). Upon GPVI ligation, Src phosphorylates Cγ2 (PLCγ2), leading to its and subsequent calcium , granule release, and αIIbβ3 , all essential for stable formation under arterial shear conditions. Inhibition of Src with impairs these processes, reducing platelet aggregation and clot stability in response to or , thereby attenuating in preclinical models. In myocardial ischemia, particularly following , Src activation exacerbates tissue damage by promoting cardiomyocyte through pathways involving (STAT3). Post-infarct Src upregulation in cardiomyocytes triggers STAT3 , which in this context contributes to pro-apoptotic signaling under , increasing and impairing recovery. Recent studies from 2023 to 2025 have further linked Src-mediated of channels, such as 43 and voltage-gated potassium channels, to disrupted electrical conduction and heightened susceptibility in ischemic hearts. For instance, Src inhibition post- restores 43 localization and reduces inducible arrhythmias by mitigating these events. Src contributes to inflammatory responses by facilitating SFK-dependent neutrophil migration and cytokine production. In activated neutrophils, Src associates with focal adhesion kinase (FAK) to promote integrin-mediated adhesion and chemotaxis toward inflammatory sites, enhancing tissue infiltration during acute responses. Additionally, Src-FAK signaling drives tumor necrosis factor-α (TNF-α) release from immune cells, amplifying . In , Src hyperactivity in synovial fibroblasts supports by promoting proliferation and invasiveness, leading to formation and joint destruction; targeted Src suppression reduces these effects in preclinical arthritis models. In , endothelial Src activation enhances vascular cell adhesion molecule-1 () expression in response to proinflammatory stimuli like oxidized . This upregulation facilitates adhesion and transmigration into the subendothelial space, initiating plaque development. Src-driven signaling through pathways such as PI3K/ sustains transcription, promoting chronic inflammation and lesion progression in arterial walls.

Neurological and Other Pathologies

In neurodegenerative diseases, hyperactivation of Src kinase contributes to pathological processes. In , amyloid-β (Aβ) oligomers bind to neuronal receptors, triggering Src family tyrosine kinases that phosphorylate at residues, promoting its hyperphosphorylation and aggregation into neurofibrillary tangles. This mechanism occurs independently of fibril formation and involves specific neuronal targeting, exacerbating synaptic dysfunction and neuronal loss. Similarly, in , c-Src facilitates the cell-to-cell transmission of α-synuclein by enhancing its release from donor cells and uptake into recipient neurons, thereby promoting aggregation and formation; recent studies from 2024 highlight Src family kinases' broader role in modulating synaptic signaling that accelerates α-synuclein spreading. Src kinase plays a critical role in bone pathologies, particularly . In , Src is activated downstream of the -RANK signaling pathway, where it mediates cytoskeletal reorganization and podosome formation essential for . This pathway is hyperactivated in post-menopausal due to deficiency, which upregulates expression, leading to excessive activity and bone loss; inhibition of Src disrupts this process, reducing resorption. In metabolic disorders, Src kinase dysregulates insulin signaling, contributing to and associated hepatic . Src modulates substrate-1 , influencing downstream activation of and in insulin-responsive tissues. In the liver, saturated fatty acids from high-fat diets contribute to c-Src-mediated activation of JNK signaling, impairing insulin action and promoting hepatic and lipid accumulation leading to .

Therapeutic Targeting

Src Kinase Inhibitors

Src kinase inhibitors are primarily small-molecule compounds designed to target the ATP-binding site or allosteric regions of the Src , disrupting its catalytic activity. These inhibitors are classified based on their binding modes, with Type I inhibitors competing directly with ATP in the active conformation of the , while Type II and III inhibitors engage inactive or allosteric conformations, often extending into adjacent pockets for enhanced selectivity. Type I inhibitors, such as , are ATP-competitive agents that bind to the active (DFG-in) conformation of Src, forming key hydrogen bonds with residues in the ATP-binding cleft, including the hinge region. , approved by the FDA in 2006 for chronic myeloid leukemia (CML), exhibits high potency against Src with an IC50 of approximately 0.5 nM. Type II and III inhibitors target the inactive (DFG-out) conformation or allosteric sites, stabilizing a less catalytically active state through interactions beyond the ATP pocket. , a quinoline-based dual Src/Abl inhibitor, exemplifies Type I binding as an ATP-competitive agent that binds to the active (DFG-in) conformation of the kinase. Recent advances include proteolysis-targeting chimeras (PROTACs), such as dasatinib-based degraders, which recruit ubiquitin ligases to induce Src ubiquitination and degradation via the pathway, offering a complementary mechanism to direct inhibition. Dual inhibitors, such as NXP900, simultaneously target Src and related s like YES1 by stabilizing the closed, autoinhibited conformation through binding in the kinase domain, which prolongs on the target. Developed as a selective inhibitor, NXP900 entered phase 1 clinical trials in 2023, demonstrating sub-nanomolar potency against both Src (IC50 ≈ 2.4 nM) and YES1 (IC50 ≈ 0.47 nM). Design strategies for Src inhibitors have evolved to exploit structural features like the ATP site's hinge region for precise hydrogen bonding interactions, as highlighted in 2025 reviews emphasizing fragment-based optimization and covalent warheads for irreversible binding. Additionally, lipid-mimetic compounds target Src's myristoylation-dependent self-association, disrupting localization and oligomerization to indirectly inhibit activation without directly engaging the kinase domain.

Clinical Developments and Challenges

Dasatinib, a multi-targeted that potently inhibits Src family kinases (SFKs), has been approved for use in chromosome-positive (Ph+) (ALL), where it achieves high response rates exceeding 90% in combination with , including complete hematologic responses in up to 98% of patients and complete molecular responses in 60-74% after induction cycles. In contrast, saracatinib, a selective Src inhibitor, failed in phase II trials for solid tumors such as metastatic and , demonstrating limited efficacy with no significant benefit and notable toxicities including pulmonary issues, leading to its discontinuation in monotherapy settings. Ongoing clinical efforts include the phase 1 trial of NXP900, a novel YES1/Src inhibitor, which in 2025 interim data from dose-escalation cohorts showed robust pharmacodynamic responses and tumor regression in preclinical models of FAT1-mutated solid tumors, prompting initiation of a phase 1b expansion specifically in FAT1-altered cancers with acceptable safety profiles. Combination strategies are addressing resistance; for instance, Src inhibitors like SKI-606 synergize with MCL-1 antagonists such as S63845 to enhance cell death in acute myeloid leukemia (AML) by blocking survival pathways, while in colorectal cancer (CRC), Src inhibition potentiates BRAF inhibitors by suppressing bypass signaling in BRAF-mutant cells. Key challenges in Src-targeted therapies include off-target inhibition of other SFKs, which contributes to hematologic toxicities like observed in up to 40-50% of dasatinib-treated patients due to disruption of normal hematopoiesis. Resistance mechanisms further complicate progress, with SRC driving multidrug resistance to KRAS G12C inhibitors in non-small cell via FAK/Src-mediated bypass pathways, as demonstrated in 2025 studies showing that co-targeting Src restores sensitivity and improves outcomes in preclinical models. Biomarkers such as SRC expression and amplification are emerging predictors of therapeutic response, with 2025 pan-cancer analyses revealing that elevated SRC levels correlate with poorer across multiple tumor types and enhanced immune infiltration, supporting its use for patient stratification in Src inhibitor trials.

Protein Interactions

Key Binding Partners

The Src SH2 domain binds to phosphotyrosine (pY) residues on various partner proteins, facilitating recruitment to signaling complexes. Key examples include focal adhesion kinase (FAK) at pY397, where Src's SH2 domain directly interacts following FAK autophosphorylation, with binding affinities typically in the range of 1-10 μM as observed for Src SH2-pY interactions in general. Similarly, the Src SH2 domain associates with phosphorylated (EGFR) at sites such as pY1068 and pY1148, enabling Src activation and downstream signaling propagation, again with Kd values around 1 μM for high-affinity pY motifs. Other notable SH2 interactions include the adaptor protein Shc at pY317, linking Src to Ras/MAPK signaling pathways. Src's SH3 domain interacts with proline-rich regions (PXXP motifs) in partner proteins, promoting scaffolding without reliance on . The Ras GTPase-activating protein (RasGAP) contains such proline-rich sequences that bind the Src SH3 domain, stabilizing interactions in GTPase regulatory networks. Likewise, the regulatory subunit p85 of 3-kinase (PI3K) features N-terminal proline-rich motifs (e.g., KPRPPRPLPVAP) that engage the Src SH3 domain with affinities supporting enzymatic activation and complex formation. These SH3-mediated bindings contribute to the architectural organization of signaling platforms. The kinase domain of Src phosphorylates and interacts with substrates such as members of the Cas family, notably p130Cas (also known as BCAR1), where Src binds and phosphorylates multiple tyrosine sites (e.g., Y249, Y410) to modulate adaptor functions. Cortactin, an actin-binding protein, serves as another kinase domain substrate, with Src phosphorylating tyrosines like Y421 and Y466 to influence cytoskeletal dynamics, though the interaction is primarily through the catalytic site rather than modular domains. Negative regulation of Src involves binding and phosphorylation by C-terminal Src kinase (Csk) and Csk-homologous kinase (Chk), which target the C-terminal tyrosine Y530 in Src. Csk binds via its SH3 domain to a proline-rich region in the linker between Src's SH2 and domains, positioning the C-terminal tail for of Y530 to enforce an autoinhibited conformation; Csk's SH2 domain aids in its recruitment to membrane scaffolds via phosphotyrosines on adaptor proteins. Chk similarly phosphorylates Y530, providing redundant inhibition. Affinity purification-mass spectrometry studies have mapped the Src interactome, identifying numerous protein partners across cellular compartments, highlighting the breadth of its binding network beyond these interactions.

Functional Impacts on Cellular Processes

Src plays a pivotal role in promoting cell survival by activating the / signaling axis, which inhibits in various cellular contexts. Through phosphorylation of , Src upregulates expression, a key anti-apoptotic protein that suppresses mitochondrial outer membrane permeabilization and activation, thereby preventing . This mechanism establishes a survival threshold, particularly evident in detachment-induced (anoikis), where elevated Src activity confers resistance by sustaining prosurvival signals in suspended cells. In , Src enhances vascular development by VEGFR2, which activates downstream effectors to promote endothelial cell behaviors essential for new vessel formation. Src-mediated of VEGFR2 at specific residues facilitates receptor dimerization and signaling, leading to increased endothelial tube formation and vascular sprouting in response to VEGF stimuli. This process supports the structural assembly of capillary networks, with Src inhibition disrupting tube stability and reducing angiogenic potential in endothelial cultures. Src drives via a feedback loop involving Ras and the MAPK pathway, culminating in amplified expression to advance the G1/S transition. Activation of Src stimulates Ras guanine nucleotide exchange, propagating signals through Raf to MEK and ERK, which transcriptionally induce and promote . This amplification loop ensures sustained proliferative responses, as demonstrated in cells expressing activated Src forms that exhibit heightened levels and accelerated . For cell motility, Src initiates a cascade involving FAK and paxillin that orchestrates invadopodia formation and dynamics, enabling invasive migration. Src phosphorylates FAK at key sites, recruiting paxillin to focal adhesions and stabilizing actin-rich protrusions (invadopodia) that degrade for cell movement. Recent studies highlight how Src's modifications, such as myristoylation, enhance its localization, thereby increasing migration speed through improved spatiotemporal signaling at lipid rafts. These functional impacts of Src are highly context-dependent, varying with cellular milieu and interaction partners to either promote or restrain processes like and without fixed outcomes.

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