Affinage

TNS2

Tensin-2 · UniProt Q63HR2

Length
1409 aa
Mass
152.6 kDa
Annotated
2026-04-28
14 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNS2 (C1-TEN/Tensin2) is a focal adhesion-associated protein tyrosine phosphatase that functions as a negative feedback regulator of PI3K/Akt signaling. Its PTPase domain dephosphorylates IRS-1 at Y612, accelerating IRS-1 proteasomal degradation and thereby suppressing PI3K activity, Akt phosphorylation, and downstream signaling—effects abolished by active-site mutation (C231S)—leading to FoxO activation and skeletal muscle atrophy under glucocorticoid stimulation (PMID:23401856, PMID:15817639). TNS2 also dephosphorylates nephrin at its PI3K-binding site, redirecting PI3K toward IRS-1/mTORC1 and contributing to podocyte hypertrophy in diabetic nephropathy, while loss-of-function in mice causes nephrotic syndrome with glomerular basement membrane defects (PMID:28955049, PMID:23988887). The cellular phosphatase activity of TNS2 is gated by PtdIns(3,4,5)P3 binding to its SH2 domain, and TNS2 protein levels are regulated by p62/SQSTM1-mediated sequestration and proteasomal degradation as well as by AXL-dependent phosphorylation that dissociates TNS2 from IRS-1 (PMID:30092354, PMID:25101860, PMID:30419905).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2002 High

    Identifying TNS2 as a physical partner of the Axl RTK established that this multi-domain protein participates in receptor tyrosine kinase signaling complexes.

    Evidence Yeast two-hybrid screen and co-immunoprecipitation in mammalian cells with domain mapping

    PMID:12470648

    Open questions at the time
    • Functional consequence of TNS2–Axl interaction unknown
    • Whether Axl phosphorylates TNS2 not tested
    • Cellular context of interaction (which tissues/cell types) undefined
  2. 2005 High

    Demonstrating that TNS2 overexpression suppresses Akt phosphorylation and cell proliferation in a catalytic-cysteine-dependent manner established TNS2 as a bona fide phosphatase that negatively regulates PI3K/Akt signaling.

    Evidence Active-site C231S mutagenesis coupled with Akt kinase assays, caspase-3 activity, and proliferation/migration assays

    PMID:15817639

    Open questions at the time
    • Direct phosphatase substrate not identified
    • Lipid vs. protein phosphatase activity not distinguished
    • In vivo relevance untested
  3. 2011 Low

    NMR chemical shift assignment of the TNS2 SH2 domain provided the structural foundation for understanding how this domain engages phosphotyrosine-containing ligands and recruits partners such as DLC1.

    Evidence Triple-resonance NMR spectroscopy on recombinant SH2 domain

    PMID:21461930

    Open questions at the time
    • No functional validation or ligand-bound structure determined
    • Relevance of DLC1 recruitment to TNS2 biology not tested
    • No binding affinity measurements
  4. 2013 High

    Identification of IRS-1 Y612 as a direct TNS2 substrate and demonstration that glucocorticoid-induced TNS2 drives IRS-1 degradation, FoxO activation, and muscle atrophy provided the first substrate-specific mechanism for TNS2 phosphatase activity in metabolic regulation.

    Evidence In vitro phosphatase assay with site-directed mutagenesis, gain/loss-of-function in cell lines and mouse models

    PMID:23401856

    Open questions at the time
    • Whether TNS2 acts on other IRS-1 phosphotyrosine sites not fully resolved
    • Structural basis of substrate recognition unknown
    • Contribution relative to other phosphatases in muscle unclear
  5. 2013 Medium

    Loss-of-function studies in mice revealed that TNS2 is essential for glomerular basement membrane assembly and podocyte foot process maintenance, linking TNS2 to nephrotic syndrome in a strain-dependent manner.

    Evidence Tenc1-mutant ICGN mice on DBA/2J vs. B6 backgrounds with histological and biochemical analysis

    PMID:23988887

    Open questions at the time
    • Molecular mechanism in podocytes not reconstituted in vitro
    • Modifier genes on permissive background unidentified
    • No rescue experiment reported
  6. 2014 Medium

    Discovery that p62/SQSTM1 sequesters TNS2 into puncta and promotes its ubiquitin-dependent proteasomal degradation revealed a post-translational mechanism controlling TNS2 protein levels, particularly during muscle differentiation.

    Evidence Co-immunoprecipitation, siRNA, ubiquitination assays, proteasome inhibitor treatment, fluorescence imaging

    PMID:25101860

    Open questions at the time
    • E3 ubiquitin ligase responsible not identified
    • Direct vs. indirect p62-mediated ubiquitination not resolved
    • Physiological consequence of altered TNS2 turnover in muscle not fully demonstrated
  7. 2017 High

    Identification of nephrin as a second TNS2 PTPase substrate explained how TNS2 upregulation in diabetic kidneys redirects PI3K toward mTORC1, causing podocyte hypertrophy and proteinuria.

    Evidence In vitro phosphatase assay on nephrin, mTORC1 activity measurement, diabetic nephropathy mouse model, siRNA knockdown

    PMID:28955049

    Open questions at the time
    • Specific nephrin phosphotyrosine site targeted not pinpointed
    • Whether TNS2 inhibition reverses established diabetic nephropathy untested
    • Contribution of TNS2 vs. other phosphatases in podocytes not quantified
  8. 2017 Medium

    Pharmacological inhibition of TNS2 by DHTS improved glucose tolerance and revealed AMPK as a downstream pathway, broadening the metabolic reach of TNS2 beyond Akt.

    Evidence Small-molecule inhibitor treatment with glucose tolerance tests and AMPK activity measurement in cell and mouse models

    PMID:29259227

    Open questions at the time
    • DHTS selectivity for TNS2 over other phosphatases not rigorously established
    • Whether AMPK regulation is direct or via IRS-1 not resolved
    • Single lab finding
  9. 2018 High

    Demonstrating that PtdIns(3,4,5)P3 binding to the SH2 domain gates TNS2 cellular phosphatase activity established a lipid-sensing negative feedback loop in insulin/PI3K signaling.

    Evidence Lipid-binding assay, structure-informed mutagenesis of three basic SH2 residues, cell-based IRS-1 dephosphorylation assay

    PMID:30092354

    Open questions at the time
    • Structural model of SH2–PIP3 complex not solved
    • Whether PIP3 binding also regulates nephrin dephosphorylation untested
    • In vivo validation of the PIP3 switch not performed
  10. 2018 Medium

    Showing that AXL phosphorylates TNS2 and that this dissociates TNS2 from IRS-1 completed a receptor-to-phosphatase regulatory circuit and linked TNS2 to cancer cell glycolytic reprogramming.

    Evidence Co-immunoprecipitation and IP-Western blot in cancer cells

    PMID:30419905

    Open questions at the time
    • AXL phosphorylation sites on TNS2 not mapped
    • No in vitro kinase assay to confirm direct phosphorylation
    • Generalizability beyond the tested cancer cell lines unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of TNS2 substrate selectivity, the identity of the E3 ligase mediating p62-driven TNS2 degradation, whether the PIP3-gating mechanism applies to nephrin dephosphorylation, and whether TNS2 has additional physiological substrates beyond IRS-1 and nephrin.
  • No crystal or cryo-EM structure of full-length TNS2 or its PTP domain
  • E3 ligase for TNS2 ubiquitination unidentified
  • Comprehensive substrate profiling not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5
Partners
AXLIRS1NPHS1SQSTM1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TNS2 (C1-TEN) was identified as an intracellular binding partner for the Axl receptor tyrosine kinase (RTK), interacting via both its SH2 and PTB domains with the Axl cytoplasmic domain, as demonstrated by yeast two-hybrid screening and co-immunoprecipitation in mammalian cells. Yeast two-hybrid screen, co-immunoprecipitation, in vitro translation Biochemical and biophysical research communications High 12470648
2005 TNS2 (C1-TEN) functions as a phosphatase that negatively regulates Akt/PKB signaling; overexpression reduced Akt phosphorylation and enzymatic activity, reduced GSK3 phosphorylation, inhibited cell proliferation and migration, and increased apoptosis. Mutation of the putative active-site cysteine (C231S) fully restored Akt activation and cell proliferation, confirming phosphatase-dependent activity. Stable overexpression, active-site mutagenesis (C231S), Akt kinase assay, caspase-3 activity assay, cell proliferation and migration assays FASEB journal High 15817639
2013 TNS2 (C1-TEN) is a protein tyrosine phosphatase (PTPase) that dephosphorylates IRS-1 preferentially at Y612, thereby accelerating IRS-1 proteasomal degradation, reducing PI3K activity, activating FoxO transcription factors, and causing skeletal muscle atrophy. C1-Ten expression is upregulated by glucocorticoids and downregulated by insulin. In vitro phosphatase assay, site-directed mutagenesis, Western blot, loss-of-function and gain-of-function in cell and mouse models Molecular and cellular biology High 23401856
2013 Tenc1 (tensin2/TNS2) is required for normal assembly and maturation of the glomerular basement membrane (GBM) and maintenance of podocyte foot processes; loss of function in a susceptible genetic background (DBA/2J) leads to nephrotic syndrome with GBM abnormalities consistent with disrupted integrin signaling. Genetic mouse model (Tenc1 mutant ICGN strain on two genetic backgrounds), histological and biochemical analysis Nephron. Experimental nephrology Medium 23988887
2014 p62/SQSTM1 sequesters TNS2 (C1-TEN) into cytoplasmic puncta and promotes its ubiquitination and proteasomal degradation; p62 depletion causes C1-Ten to diffuse into the cytoplasm. This regulation is specific to C1-Ten and not to tensin1 or tensin3. p62 expression increases during muscle differentiation, correlating with decreased C1-Ten protein levels. Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, fluorescence imaging, proteasome inhibitor treatment Cellular signalling Medium 25101860
2017 TNS2 (C1-TEN) acts as a PTPase on nephrin at its PI3K binding site, redirecting PI3K toward IRS-1 and thereby activating mTORC1, leading to podocyte hypertrophy and proteinuria in diabetic kidney disease. C1-Ten levels are elevated in diabetic kidneys and high-glucose-treated podocytes. In vitro phosphatase assay with nephrin substrate, cell-based mTORC1 activity measurement, in vivo mouse model of diabetic nephropathy, siRNA knockdown Scientific reports High 28955049
2017 Pharmacological inhibition of TNS2 (C1-TEN) PTPase activity by 15,16-dihydrotanshinone I (DHTS) increases IRS-1 stability, improves glucose tolerance, and reveals a new function of C1-Ten in AMPK inhibition, suggesting C1-Ten regulates AMPK signaling possibly through IRS-1. Small-molecule inhibitor treatment, glucose tolerance assay, IRS-1 stability assay, AMPK activity measurement in cell and mouse models Scientific reports Medium 29259227
2018 The cellular phosphatase activity of TNS2 (C1-Ten/Tensin2) on IRS-1 is controlled by binding of the C1-Ten SH2 domain to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), forming a negative feedback loop in insulin signaling. Three basic residues in the SH2 domain critical for PtdIns(3,4,5)P3 binding (but not phosphotyrosine binding or PTP activity) were identified by mutagenesis; a PtdIns(3,4,5)P3 binding-deficient mutant abolished cellular PTP activity toward IRS-1. Lipid-binding assay, site-directed mutagenesis, in vitro phosphatase assay, cell-based IRS-1 dephosphorylation assay, PI3K inhibition experiments Cellular signalling High 30092354
2018 AXL receptor tyrosine kinase phosphorylates TNS2, and this phosphorylation releases TNS2 from interaction with IRS-1, thereby increasing IRS-1 stability. The AXL/TNS2/IRS-1 cross-talk upregulates aerobic glycolysis enzymes Glut4 and PDK1 in cancer cells. Co-immunoprecipitation, IP-Western blot, Western blot for phosphorylation substrates Journal of biomedical science Medium 30419905
2011 Complete NMR chemical shift assignments of the SH2 domain of human TNS2 (TENC1) were determined, providing a structural basis for understanding its interactions with tyrosine-phosphorylated proteins and DLC1 recruitment to focal adhesions in a phosphotyrosine-independent manner. Triple-resonance NMR spectroscopy (1H, 15N, 13C chemical shift assignment) Biomolecular NMR assignments Low 21461930

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 79 15817639
2002 Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin. Biochemical and biophysical research communications 69 12470648
2013 C1-Ten is a protein tyrosine phosphatase of insulin receptor substrate 1 (IRS-1), regulating IRS-1 stability and muscle atrophy. Molecular and cellular biology 34 23401856
2013 Tenc1-deficient mice develop glomerular disease in a strain-specific manner. Nephron. Experimental nephrology 19 23988887
2018 AXL phosphorylates and up-regulates TNS2 and its implications in IRS-1-associated metabolism in cancer cells. Journal of biomedical science 17 30419905
2017 Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways. Scientific reports 17 29259227
2021 Immunohistochemical Analysis of the Expression of Adhesion Proteins: TNS1, TNS2 and TNS3 in Correlation with Clinicopathological Parameters in Gastric Cancer. Biomolecules 16 33926026
2017 C1-Ten is a PTPase of nephrin, regulating podocyte hypertrophy through mTORC1 activation. Scientific reports 16 28955049
2018 Cellular phosphatase activity of C1-Ten/Tensin2 is controlled by Phosphatidylinositol-3,4,5-triphosphate binding through the C1-Ten/Tensin2 SH2 domain. Cellular signalling 13 30092354
2014 Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated sequestration and degradation. Cellular signalling 3 25101860
2011 1H, 15N and 13C chemical shift assignments of the SH2 domain of human tensin2 (TENC1). Biomolecular NMR assignments 2 21461930
2026 Hypothalamic-Pituitary Deficiency after Radiation in Childhood Cancer Survivors is Associated with Rare Variants in TNS2. The Journal of clinical endocrinology and metabolism 0 41739851
2026 TNS1 and TNS4 play a potential role in development of pancreatic ductal adenocarcinoma but not TNS2 and TNS3. Cell adhesion & migration 0 41923376
2025 Adult-Onset Nephrotic Syndrome due to a Homozygous TNS2 Truncating Variant: Broadening the Mutational Spectrum. Clinical genetics 0 40865979