Affinage

TLN2

Talin-2 · UniProt Q9Y4G6

Round 2 corrected
Length
2542 aa
Mass
271.6 kDa
Annotated
2026-04-28
42 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLN2 (Talin-2) is a large cytoskeletal adaptor protein that couples integrin cytoplasmic tails to the actin cytoskeleton, functioning as the predominant talin isoform in striated muscle. Its N-terminal FERM domain binds β-integrin tails with isoform-specific affinity — particularly high for β1D-integrin in muscle — while its C-terminal I/LWEQ module mediates F-actin binding, filament stabilization, and dimerization, all subject to intrasteric autoinhibition (PMID:9159132, PMID:15581353, PMID:21134644). In adult cardiomyocytes, TLN2 is the dominant costameric talin; stress-induced upregulation of TLN1 (not TLN2) drives hypertrophic ERK/Akt signaling, establishing non-redundant roles for the two isoforms (PMID:23266827). A missense variant in the TLN2 FERM domain (p.S339L) co-segregates with autosomal dominant fifth finger camptodactyly (PMID:27223613).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1997 High

    Identification of the conserved I/LWEQ module as the F-actin-binding domain of talins established the molecular basis for how talin family members, including TLN2, link integrins to the actin cytoskeleton.

    Evidence In vitro F-actin competition assays and site-directed mutagenesis of a conserved residue in the fourth block of the I/LWEQ module

    PMID:9159132

    Open questions at the time
    • The study characterized shared talin family features; TLN2-specific regulation was not addressed
    • No structural model of the full-length talin–actin complex was available
  2. 2001 High

    Cloning and expression profiling of TLN2 revealed it as a second talin gene with high sequence conservation to TLN1 but distinct tissue expression dominated by the heart, establishing TLN2 as a muscle-enriched isoform.

    Evidence Genomic/EST database assembly and Northern blot expression analysis across tissues

    PMID:11527381

    Open questions at the time
    • No functional distinction between TLN1 and TLN2 at the protein level was yet demonstrated
    • Protein-level expression and localization in muscle were not characterized
  3. 2004 High

    Biochemical dissection of the TLN2 I/LWEQ module revealed that its F-actin binding is autoinhibited by an upstream structural element, and the module also mediates dimerization and stabilizes actin filaments, explaining how talin activity is regulated and how it reinforces the cytoskeleton.

    Evidence F-actin co-sedimentation, quantitative affinity measurements, and truncation analysis of the TLN2 C-terminal domain

    PMID:15581353

    Open questions at the time
    • The mechanism of autoinhibition release in cells was not determined
    • Structural details of the dimerization interface were not resolved
  4. 2010 High

    NMR structural analysis demonstrated that the TLN2 FERM domain binds the β1D-integrin cytoplasmic tail with unusually high affinity compared to other talin–integrin combinations, providing the structural basis for isoform-specific integrin activation in striated muscle.

    Evidence NMR spectroscopy and thermodynamic binding measurements across multiple talin/integrin isoform pairs

    PMID:21134644

    Open questions at the time
    • Functional consequences of this high-affinity interaction in intact muscle were not tested
    • Whether TLN2-specific residues outside the FERM domain contribute to muscle specificity was not addressed
  5. 2012 High

    In vivo genetic studies established that TLN2 is the predominant costameric talin in adult cardiomyocytes and that stress-induced TLN1 upregulation (not TLN2) drives maladaptive hypertrophic signaling through ERK, Akt, and p38, demonstrating non-redundant cardiac functions of the two isoforms.

    Evidence Cardiomyocyte-specific Tln1 conditional knockout mice subjected to pressure overload, with immunofluorescence and signaling pathway analysis

    PMID:23266827

    Open questions at the time
    • Cardiomyocyte-specific Tln2 knockout was not reported, so TLN2-specific cardiac function remained undefined
    • The mechanism by which TLN1 preferentially activates hypertrophic signaling cascades versus TLN2 was not resolved
  6. 2016 Medium

    A FERM-domain missense variant (p.S339L) in TLN2 was linked to autosomal dominant fifth finger camptodactyly, providing the first genetic evidence that TLN2 dysfunction causes a human skeletal phenotype.

    Evidence Exome sequencing with co-segregation in a four-generation family; wild-type and mutant TLN2 expression in HEK293 cells

    PMID:27223613

    Open questions at the time
    • Functional impact of S339L on integrin binding or cytoskeletal coupling was not measured
    • Incomplete penetrance mechanism is unexplained
    • No independent replication in additional families
  7. 2018 Medium

    The discovery that TLN2 physically interacts with WWC1/KIBRA in brain tissue and modulates Tau toxicity in Drosophila extended TLN2's functional repertoire beyond integrin–actin coupling to neurodegeneration-relevant signaling.

    Evidence Reciprocal co-immunoprecipitation from brain tissue and HEK293 cells, co-localization imaging, Drosophila Tau genetic interaction assay

    PMID:30201328

    Open questions at the time
    • The binding interface and domain requirements for the TLN2–WWC1 interaction are unknown
    • Whether this interaction modulates Hippo/YAP signaling in the brain was not tested
    • The mechanistic basis by which TLN2–WWC1 modulates Tau toxicity is undefined
  8. 2022 Medium

    Functional studies in clear cell renal cell carcinoma cells showed that TLN2 suppresses proliferation, invasion, and migration through inactivation of Wnt/β-catenin signaling, revealing a potential tumor-suppressive role.

    Evidence Overexpression/knockdown in ccRCC lines, multiple cellular assays, xenograft, and Wnt pathway reporter analysis

    PMID:35242640

    Open questions at the time
    • The direct biochemical mechanism connecting TLN2 to Wnt/β-catenin pathway inhibition is unknown
    • Relevance to normal kidney physiology versus cancer-specific context is unclear
    • Single study without independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the in vivo consequence of cardiomyocyte-specific TLN2 loss, the structural basis of autoinhibition release, and whether TLN2's non-canonical interactions (WWC1, Wnt pathway) reflect direct signaling functions or indirect cytoskeletal effects.
  • No cardiomyocyte-specific Tln2 knockout phenotype reported
  • Full-length TLN2 structure with autoinhibited-to-active transition not resolved
  • Mechanistic links between TLN2 and Wnt or Hippo pathways require biochemical reconstitution

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005856 cytoskeleton 3 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1474244 Extracellular matrix organization 2 R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 2
Partners
ACTBITGB1TLN1WWC1

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 The C-terminal I/LWEQ module of talin (shared by TLN1 and TLN2) constitutes a conserved F-actin binding domain. In vitro competition assays showed the isolated I/LWEQ module competes quantitatively with native talin for F-actin binding, and mutation of a conserved residue in the fourth block abolishes actin interaction. In vitro F-actin binding competition assay, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 9159132
2001 TLN2 encodes a protein of similar size and sequence to talin1 (74% identity, 86% similarity) throughout its length, with strictly conserved intron/exon boundaries (except two). Unlike TLN1 which produces a single ~8 kb ubiquitous mRNA, TLN2 produces multiple transcripts with highest expression in heart, indicating distinct tissue-specific expression patterns. Genomic and EST database assembly, Northern blot/expression analysis Biochemical and biophysical research communications High 11527381
2004 Talin2's actin-binding capacity is regulated by intrasteric occlusion: a structural element upstream of the I/LWEQ module inhibits actin binding by cryptically masking the primary actin-binding determinants. Additionally, the I/LWEQ module of Talin2 contains a dimerization motif and stabilizes actin filaments against depolymerization. F-actin co-sedimentation assay, affinity measurements, truncation and domain analysis of Talin2 I/LWEQ module Biochemistry High 15581353
2010 The Talin2 FERM domain interacts with β1D-integrin cytoplasmic tail with unusually high affinity. NMR structural analysis revealed that the Talin2/β1D isoform pair, which co-localizes in striated muscle, forms a tighter interaction than other talin/integrin combinations, suggesting isoform-specific fine-tuning of integrin activation in muscle. NMR spectroscopy, binding affinity measurements, structural analysis of talin/integrin tail complexes Structure (London, England : 1993) High 21134644
2012 In the adult mouse heart, Talin2 (but not Talin1) is the predominant talin isoform in cardiomyocytes, localizing to costameres. During pressure overload or pharmacological stress, Talin1 is up-regulated and recruited to costameres. Cardiomyocyte-specific Tln1 knockout mice show blunted hypertrophy, reduced fibrosis, and improved cardiac function after pressure overload, with strongly blunted acute ERK1/2, p38, Akt, and GSK3 signaling responses. Cardiomyocyte-specific conditional knockout (Tln1cKO), pressure overload model, immunofluorescence localization, western blot signaling analysis The Journal of biological chemistry High 23266827
2018 TLN2 (Talin2) physically interacts with WWC1/KIBRA as demonstrated by co-immunoprecipitation from both brain tissue and HEK293 cells, and the two proteins co-localize in brain tissue cells, N2a neuroblastoma, and HeLa cell lines. In Drosophila eye experiments, co-expression of WWC1/KIBRA and TLN2 modulated Tau toxicity, suggesting a functional interaction relevant to neurodegeneration. Co-immunoprecipitation from brain tissue and HEK293 cells, co-immunofluorescence localization, Drosophila Tau toxicity genetic interaction assay Neurobiology of aging Medium 30201328
2016 A missense variant in TLN2 (c.1016C>T, p.S339L) located in the FERM domain was identified as a cause of autosomal dominant fifth finger camptodactyly with incomplete penetrance in a four-generation Chinese Han family. Expression of wild-type and mutant TLN2 in HEK293 cells showed predominant cytoplasmic localization for both, suggesting the mutation does not dramatically alter subcellular targeting. Exome sequencing, Sanger sequencing co-segregation analysis, expression of wild-type and mutant TLN2 in HEK293 cells with localization assessment PloS one Medium 27223613
2022 TLN2 overexpression in clear cell renal cell carcinoma (ccRCC) cells inhibits proliferation, invasion, migration, promotes apoptosis, and inhibits cell cycle progression. Mechanistically, TLN2 was shown to exert these anti-tumor functions through inactivation of the Wnt/β-catenin signaling pathway, as assessed by pathway reporter and downstream target analysis. Overexpression and knockdown in ccRCC cell lines, CCK-8, colony formation, transwell, wound healing, apoptosis/cell cycle assays, in vivo xenograft, Wnt/β-catenin pathway analysis Translational andrology and urology Medium 35242640

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. Nature cell biology 490 21423176
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2002 Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 396 12422220
2002 Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin. Nature 389 12422219
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2004 An investigation into the human serum "interactome". Electrophoresis 247 15174051
1997 Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 187 9205841
2004 Cytoskeletal proteins talin and vinculin in integrin-mediated adhesion. Biochemical Society transactions 153 15494027
1997 The I/LWEQ module: a conserved sequence that signifies F-actin binding in functionally diverse proteins from yeast to mammals. Proceedings of the National Academy of Sciences of the United States of America 149 9159132
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2010 Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease. NeuroImage 121 20197096
2021 Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 113 34349018
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2001 Analysis of the mammalian talin2 gene TLN2. Biochemical and biophysical research communications 98 11527381
1999 Integrin-mediated cell adhesion: the cytoskeletal connection. Biochemical Society symposium 88 10320934
2010 Structural diversity in integrin/talin interactions. Structure (London, England : 1993) 80 21134644
2013 A genome-wide association study of sleep habits and insomnia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 79 23728906
2021 UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex. Cell stem cell 78 33417871
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2012 Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload. The Journal of biological chemistry 70 23266827
2004 Intrasteric inhibition mediates the interaction of the I/LWEQ module proteins Talin1, Talin2, Hip1, and Hip12 with actin. Biochemistry 67 15581353
2004 A role for talin in presynaptic function. The Journal of cell biology 66 15479735
1999 Functional genomic analysis reveals the utility of the I/LWEQ module as a predictor of protein:actin interaction. Biochemical and biophysical research communications 45 10581178
2007 A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin. Biochemistry 41 17722883
2018 Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. Neurobiology of aging 26 30201328
2006 The conserved C-terminal I/LWEQ module targets Talin1 to focal adhesions. Cell motility and the cytoskeleton 22 16830345
2016 Exome Sequencing of a Pedigree Reveals S339L Mutation in the TLN2 Gene as a Cause of Fifth Finger Camptodactyly. PloS one 9 27223613
2022 TLN2 functions as a tumor suppressor in clear cell renal cell carcinoma via inactivation of the Wnt/β-catenin signaling pathway. Translational andrology and urology 8 35242640
2020 Long Noncoding RNA Lnc-TLN2-4:1 Suppresses Gastric Cancer Metastasis and Is Associated with Patient Survival. Journal of oncology 8 32256587
2014 The I/LWEQ domain in RapGAP3 required for posterior localization in migrating cells. Molecules and cells 3 24608804
2017 Minimal amino acids in the I/LWEQ domain required for anterior/posterior localization in Dictyostelium. Journal of microbiology (Seoul, Korea) 1 28124777