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TENC1
TENC1
TENC1
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TNS2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTNS2, C1-TEN, C1TEN, TENC1, tensin 2
External IDsOMIM: 607717; MGI: 2387586; HomoloGene: 37077; GeneCards: TNS2; OMA:TNS2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

23371

209039

Ensembl

ENSG00000111077

ENSMUSG00000037003

UniProt

Q63HR2

Q8CGB6

RefSeq (mRNA)

NM_015319
NM_170754
NM_198316

NM_153533
NM_001355636

RefSeq (protein)

NP_056134
NP_736610
NP_938072

NP_705761
NP_001342565

Location (UCSC)Chr 12: 53.05 – 53.06 MbChr 15: 102.01 – 102.02 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Tensin-like C1 domain-containing phosphatase is an enzyme that in humans is encoded by the TENC1 gene.[5]

The protein encoded by this gene belongs to the tensin family. Tensin is a focal adhesion molecule that binds to actin filaments and participates in signaling pathways. This protein plays a role in regulating cell migration. Alternative splicing occurs at this locus and three transcript variants encoding three distinct isoforms have been identified.[5]

Interactions

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TENC1 has been shown to interact with AXL receptor tyrosine kinase.[6]

References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

TENC1

View on Grokipedia
from Grokipedia
TENC1, also known as TNS2, is a protein-coding located on human chromosome 12q13.13 that encodes tensin-2, a member of the tensin family of adaptor proteins. Tensin-2 binds to filaments at focal adhesions and functions as a tyrosine-protein , regulating key cellular processes including , proliferation, and insulin responsiveness in muscle tissue. The protein contains conserved domains such as an , a PTEN-like homology region, an , and a phosphotyrosine-binding (PTB) domain, which facilitate its interactions with , cytoskeletal elements, and signaling molecules like PI3K and SYK kinase. TNS2 is broadly expressed, with highest levels in the heart, , kidney, and liver, and lower expression in , colon, , and leukocytes. In the kidney, tensin-2 is particularly critical for maintaining podocyte morphology, adhesion to the , and the integrity of the glomerular filtration barrier. It promotes through focal adhesion dynamics and suppresses tumorigenesis by modulating interactions with tumor suppressors and oncoproteins. Alternative splicing of TNS2 yields at least three isoforms, with the full-length protein comprising 1,285 to 1,419 . Mutations in TNS2 have been linked to renal disorders, including forms of such as characterized by glomerular sclerosis and , as well as adult-onset cases due to truncating variants, as observed in both models and human patients. For instance, an 8-nucleotide deletion in the mouse Tns2 leads to loss of protein expression and spontaneous development of , highlighting its non-redundant role among tensin family members in kidney function. Downregulation of TNS2 has also been implicated in cancer progression, such as colorectal and cancers, where reduced expression correlates with increased tumorigenicity and poorer relapse-free survival.

Genetics

Gene location and organization

The TENC1 gene, officially designated as TNS2 (tensin 2), is situated on the long arm of human chromosome 12 at the cytogenetic band 12q13.13. In the GRCh38.p14 reference genome assembly, it occupies the genomic coordinates 53,046,991 to 53,064,379 on the forward strand, spanning approximately 17 kb of DNA sequence. The gene is organized into 32 exons, with alternative splicing generating 23 distinct transcripts and at least six protein-coding isoforms. Upstream of the coding region, TENC1 includes promoter sequences and associated regulatory elements, such as enhancers, which modulate transcriptional activity as annotated in genomic databases. TENC1 exhibits strong evolutionary conservation, with orthologs present in 114 , including mammals; for instance, the ortholog Tns2 maps to the telomeric region of 15. The was initially identified and designated TENC1 (tensin-like C1 domain-containing ) in 1999, later recognized as synonymous with TNS2, and assigned HGNC ID 19737 and OMIM entry 607717.

Isoforms and expression patterns

The TENC1 gene, also known as TNS2, undergoes to produce multiple transcript variants. Ensembl annotations indicate a total of 23 transcripts, with at least six protein-coding isoforms identified, arising from variations in inclusion and exclusion. The isoform, often referred to as C1-TEN, encodes a full-length protein with intact activity, featuring key domains such as the C1, SH2, and PTP domains essential for its regulatory functions. Other isoforms differ primarily in their N-terminal regions or inclusion of specific exons, potentially altering subcellular localization or interaction profiles, though all retain core structural elements. Expression of TENC1 is ubiquitous across human tissues, detectable in at least 25 tissues based on RNA-seq data from the GTEx . Highest expression levels are observed in (median RPKM 68.0), followed by (RPKM 31.0) and (RPKM approximately 25-30), reflecting its potential roles in metabolic and cytoskeletal processes in these sites. In contrast, expression is notably lower in regions (RPKM <5) and liver (RPKM ~10), suggesting tissue-specific regulatory mechanisms that modulate its abundance. TENC1 expression is dynamically regulated during developmental stages. In skeletal muscle, C1-TEN mRNA levels are high in late embryonic (E17.5) and newborn (P0) stages but decrease significantly by postnatal day 21 (P21). Environmental factors, such as insulin signaling, further influence its expression in muscle; insulin stimulation can modulate TENC1 levels via feedback on the pathway, contributing to metabolic . These patterns highlight TENC1's responsiveness to both ontogenetic cues and physiological signals.

Protein

Structure and domains

The TENC1 gene encodes Tensin-2, a multidomain protein comprising 1409 in its canonical isoform, which functions as a molecular bridge linking the to the . This architectural organization enables Tensin-2 to integrate signaling and structural elements within . At the N-terminus, Tensin-2 features a C1 domain (also termed a PH-like domain) that mediates lipid binding, facilitating membrane association. The central region contains a (PTP) domain, spanning approximately residues 500–700, which catalyzes the of residues on target substrates. Toward the C-terminus, an —whose solution structure has been elucidated by NMR (PDB ID: 2KNO)—recognizes phosphotyrosine motifs, while an adjacent PTB domain binds tails, anchoring the protein to adhesion complexes. Post-translational modifications of Tensin-2 include sites within the SH2 and PTP domains, which regulate domain interactions and activity, whereas no prominent events have been identified. Alternative isoforms arising from splicing may variably include or exclude certain domains, potentially altering protein localization.

Biochemical properties

TENC1 encodes C1-TEN (also known as Tensin-2), a tyrosine-specific featuring a catalytic (PTP) domain that hydrolyzes phosphotyrosine residues on substrates such as (IRS-1). This activity negatively regulates insulin signaling by dephosphorylating IRS-1, thereby influencing cell proliferation, motility, and insulin responsiveness in muscle tissue. The PTP domain's function is enhanced by the protein's Src-homology 2 (, which binds phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) to localize and activate the at lipid-enriched membrane sites. C1-TEN demonstrates high-affinity binding to actin filaments via its C-terminal actin-binding domain, enabling its to cytoskeletal structures and focal adhesions where it modulates cytoskeletal dynamics. The C1 domain facilitates interactions with , contributing to the protein's association, though specific binding partners beyond general diacylglycerol-like molecules remain less characterized. As a classical PTP, C1-TEN's activity is potently inhibited by , a common orthovanadate-based inhibitor that targets the catalytic residue in the PTP . The protein localizes primarily to the and s, with its stability and activity influenced by cellular lipid environments. generates multiple isoforms, some of which retain the full PTP domain while others may exhibit reduced enzymatic efficiency due to domain truncation.

Biological function

Role in and migration

TENC1, also known as TNS2 or tensin-2, functions as a protein that links receptors to the , thereby stabilizing adhesions essential for cellular movement. Through its phosphotyrosine-binding (PTB) domain, TENC1 binds to the cytoplasmic tails of β- subunits, while its Src homology 2 ( interacts with phosphotyrosine residues on adhesion components, facilitating the connection between the and F-actin bundles. This structural bridging supports the assembly and maturation of s in various cell types, including fibroblasts and epithelial cells. In regulating , TENC1 promotes by enhancing the dynamics of leading-edge protrusions and turnover on substrates like . Overexpression of TENC1 in HEK293 cells accelerates migration in Boyden chamber assays, indicating a positive role in directed cell movement. Conversely, its effects are context-dependent; knockdown in cancer cells enhances proliferation and tumorigenicity, suggesting TENC1 can suppress excessive in transformed cells. Its actin-binding domain at the directly interacts with F-actin bundles, influencing assembly and cytoskeletal remodeling during translocation. In tissue-specific contexts, TENC1 is critical for maintaining glomerular integrity in podocytes, where it reinforces podocyte-glomerular (GBM) interactions via integrin-α3β1. Deficiency in TENC1 leads to weakened to , GBM thickening, and progressive in models, underscoring its role in preserving the barrier under mechanical stress. Knockdown in podocyte cell lines enhances actin formation and , implying TENC1 normally restrains cytoskeletal rearrangements to support stationary in this specialized .

Involvement in signaling pathways

TENC1, also known as TNS2 or C1-TEN, plays a multifaceted role in intracellular signaling networks, primarily through its (PTPase) activity and interactions at focal adhesions. In the Akt pathway, TENC1 generally acts as a negative regulator by reducing Akt and enzymatic activity, thereby inhibiting downstream effects on cell survival and proliferation; however, in the context of thrombopoietin (TPO) signaling via the c-Mpl receptor, TENC1 enhances TPO-induced Akt activation, promoting megakaryocyte proliferation through stabilization of the pathway. In insulin signaling, TENC1 modulates responses to insulin by dephosphorylating insulin receptor substrate 1 (IRS-1), which attenuates PI3K/Akt activation and limits and metabolic effects; this negative regulation helps prevent excessive signaling under normal conditions but can contribute to when dysregulated. TENC1 participates in integrin-mediated signaling as a adaptor, linking activation to cytoskeletal dynamics and transducing mechanical cues into biochemical responses that influence cell spreading and motility, often in coordination with Rab25-dependent integrin internalization. Additionally, TENC1 contributes to PTEN-related phosphoinositide regulation by binding 3,4,5-trisphosphate (PIP3) via its , reducing PIP3 levels at the plasma membrane and dampening PI3K-driven signals in a manner complementary to PTEN's lipid phosphatase function. Through feedback mechanisms, TENC1 fine-tunes (RTK) signaling by dephosphorylating substrates, which limits prolonged activation and prevents over-stimulation of downstream pathways like PI3K/Akt in response to growth factors. In podocyte-specific contexts, TENC1 dephosphorylates nephrin at its PI3K-binding site, disrupting the nephrin-PI3K complex and redirecting PI3K to IRS-1, thereby activating and influencing glomerular signaling balance. Its actin-binding capability facilitates localization to signaling hubs at focal adhesions, enabling context-dependent pathway modulation.

Molecular interactions

Protein-protein partners

TENC1, also known as TNS2 or tensin-2, engages in several key protein-protein interactions that facilitate its roles in focal adhesions and signaling. As a member of the tensin family, it binds to the , where TNS2 at Y483 and influences downstream metabolic signaling in cancer cells. Among kinase partners, TENC1 interacts directly with SYK, a , resulting in SYK and localization to focal adhesions in epithelial cells. Additionally, TENC1 binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), bridging metabolic enzymes with signaling components and regulating through phosphorylation-dependent mechanisms. TENC1 also associates with adapter proteins, notably SQSTM1 (p62), where SQSTM1 sequesters TENC1 into cytoplasmic puncta via SQSTM1's PB1 domain and promotes TENC1 ubiquitination and proteasomal degradation. Furthermore, as an integrin adaptor, TENC1 interacts with β1-s via its PTB domain, stabilizing their activity and supporting fibrillar adhesion formation in response to cues.

Regulatory mechanisms

The activity and localization of TENC1 (also known as C1-Ten or Tensin-2) are tightly regulated through multiple post-translational modifications that modulate its function and interactions within focal adhesions. Phosphorylation of TENC1 at residue Y483 by SRC family kinases and enhances the binding affinity of its to phosphotyrosine-containing substrates, thereby activating its role in dephosphorylating targets such as IRS-1 and influencing insulin signaling pathways. This is essential for recruiting TENC1 to rafts enriched in phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), where the binds with high affinity (Kd ≈ 260 nM), facilitating its activity on IRS-1 at Y612. Additionally, ubiquitination of TENC1 promotes its proteasomal degradation, serving as a mechanism to control protein levels and prevent excessive activity that could disrupt signaling balance. Transcriptional regulation of TENC1 expression responds to environmental cues, with upregulation observed in contexts of metabolic stress such as high glucose conditions in , contributing to diabetic by enhancing nephrin and . Compartmentalization plays a critical role in TENC1 function, with SQSTM1 (p62) sequestering TENC1 into cytoplasmic puncta, thereby restricting its availability at focal adhesions and modulating cytoskeletal dynamics. This SQSTM1-mediated sequestration specifically targets TENC1 for autophagic processing and degradation, distinct from other tensin family members like TNS1 and TNS3, and is particularly prominent during processes such as , where increased SQSTM1 levels correlate with reduced TENC1. Release from these puncta, as seen upon SQSTM1 depletion, disperses TENC1 into the , potentially facilitating its recruitment to focal adhesions during . Brief interactions with partners like , which phosphorylates TENC1, further fine-tune this compartmental control. Inhibitory mechanisms directly target the (PTP) domain of TENC1 to dampen its enzymatic activity. , acting as a phosphotyrosine mimetic, inhibits TENC1 PTPase function by disrupting its interaction with substrates like IRS-1, thereby stabilizing and enhancing insulin signaling. Similarly, inactivates the PTP domain through reversible oxidation of the catalytic residue, a common regulatory switch for PTPs that limits TENC1's capacity under imbalance. These inhibitions collectively prevent aberrant signaling, ensuring TENC1's activity aligns with cellular needs.

Clinical and research aspects

Disease associations

Mutations in the TNS2 gene, encoding tensin-2 (also known as TENC1), have been identified as a cause of , particularly in cases presenting with steroid-resistant and glomerular sclerosis. These mutations disrupt dynamics in podocytes, leading to impaired glomerular filtration barrier integrity and subsequent heavy , often manifesting in childhood or adulthood depending on the variant type. For instance, homozygous or compound heterozygous missense mutations in TNS2 have been reported in families with partially treatment-sensitive , highlighting its role in a shared pathogenic pathway involving regulation. A 2025 described adult-onset resulting from a homozygous null in TNS2, indicating that complete loss-of-function variants can manifest later in life. Beyond renal pathologies, TNS2 has potential implications in cancer proliferation, where it modulates thrombopoietin (TPO)-induced signaling via promotion of Akt activation, influencing and survival in hematopoietic and other malignancies. Downregulation of TNS2 has been linked to enhanced tumorigenicity through upregulation of Akt, MEK, and IRS1 pathways in various lines. Additionally, altered TNS2 expression may contribute to thrombopoietin-related disorders by affecting proliferation and platelet production. No Mendelian diseases are definitively confirmed for TNS2 in OMIM, indicating that its disease associations are primarily through rare variants rather than classic monogenic inheritance.

Model organism studies and therapeutic implications

Studies in s have provided key insights into the role of TENC1 (also known as TNS2) in renal function and pathogenesis. In mice, Tenc1-knockout models demonstrate strain-specific glomerular pathology. For instance, Tenc1-deficient mice on the FVB/N background develop severe glomerular characterized by , , and progressive renal failure, with histological features including thickened glomerular basement membranes and foot process effacement. In contrast, on the background, these knockouts exhibit milder or no overt renal defects even after extended observation periods, highlighting the influence of genetic on penetrance. The ICGN mouse , which carries a spontaneous Tenc1 , recapitulates with and effacement, leading to death by approximately 26 weeks of age. Beyond murine models, studies using cell lines have elucidated TENC1's contributions to cellular processes relevant to renal health. Silencing of TENC1 in cell lines, such as fibroblasts and epithelial cells, impairs , as TENC1 positively regulates migration through its interactions at focal adhesions. Although direct ortholog knockdown studies in for TENC1 are limited, related tensin family members like TNS1 influence cardiac and potentially renal , suggesting conserved roles in organ development that warrant further exploration in TENC1-specific models. Therapeutic implications emerging from these models center on modulating TENC1-related pathways to mitigate renal disorders. In Tenc1-mutant mice, treatment with dihydro-CDDO-trifluoroethyl , an antioxidant inflammation modulator, reduces tubular damage, , and , indicating potential for targeting in TENC1 deficiency-associated . For cancers where TENC1 promotes proliferation, such as certain gastrointestinal stromal tumors, small-molecule inhibitors of TENC1 or its downstream effectors like DLC1 could suppress tumor growth, though context-dependent effects require careful validation. approaches, aimed at restoring TENC1 expression in podocytes, hold promise for treating hereditary renal disorders linked to TENC1 variants, building on successes in other monogenic diseases. Despite these advances, significant research gaps persist. Human mutations in TENC1 remain rare, with only a handful of families reported, limiting genotype-phenotype correlations and translation from animal models. Additionally, the functional distinctions among TENC1 isoforms, particularly regarding its pseudophosphatase (PTP) domain activity, are underexplored, as studies show conflicting requirements for PTP in renal protection versus cellular regulation. Isoform-specific investigations in advanced models could clarify these nuances and guide precision therapies.

References

  1. https://www.ncbi.nlm.nih.gov/gene/23371
  2. https://www.uniprot.org/uniprotkb/Q63HR2/entry
  3. https://omim.org/entry/607717
  4. https://journals.lww.com/jasn/fulltext/2022/11001/new_mutation_in_the_tns2_gene_causes_a_new_form_of.2870.aspx
  5. https://onlinelibrary.wiley.com/doi/abs/10.1111/cge.70053
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC5122378/
  7. https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000111077
  8. https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:19737
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC6392469/
  10. https://gtexportal.org/home/gene/TNS2
  11. https://www.proteinatlas.org/ENSG00000111077-TNS2/tissue
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC3624259/
  13. https://www.sciencedirect.com/science/article/abs/pii/S0898656818301669
  14. https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNS2
  15. https://maayanlab.cloud/Harmonizome/gene/TNS2
  16. https://journals.biologists.com/jcs/article/134/4/jcs254029/237381/Tensins-emerging-insights-into-their-domain
  17. https://www.rcsb.org/structure/2KNO
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC10660079/
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