Affinage

TLN2

Talin-2 · UniProt Q9Y4G6

Length
2542 aa
Mass
271.6 kDa
Annotated
2026-06-10
49 papers in source corpus 14 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLN2 encodes talin2, a cytoskeletal adaptor that couples β-integrins to the actin cytoskeleton and is enriched in striated muscle and stable adhesion structures (PMID:11527381, PMID:17183545). During myoblast differentiation talin2 is upregulated and relocates to costameres and intercalated disks—the stable adhesion complexes of mature muscle—whereas talin1 marks the focal adhesions of undifferentiated cells (PMID:17183545). Talin2 binds β1-integrin tails more strongly than talin1 owing to a unique S339–E353 hydrogen-bond network that positions talin2 N326/K327 against β1-integrin R760/D759; disrupting Ser339 (S339C or the disease variant S339L) abolishes this high-affinity binding (PMID:27694340, PMID:28155884). In the heart talin2 is the dominant costameric isoform postnatally and maintains β1D-integrin levels, but its loss is tolerated through compensatory talin1 upregulation, while combined cardiomyocyte loss of both isoforms collapses costameric integrity and causes lethal dilated cardiomyopathy (PMID:28698364). In cancer cells talin2 localizes to invadopodia where its high β-integrin affinity drives traction-force generation and matrix degradation required for invasion, a function talin1 cannot substitute (PMID:27694340). Talin2 is also required for myofibroblast differentiation and the pro-fibrotic program; its loss confers resistance to and reverses experimental lung and kidney fibrosis (PMID:40410300). A missense TLN2 variant p.S339L co-segregates with Fifth Finger Camptodactyly (PMID:27223613). Additional roles include modulation of tau toxicity through interaction with WWC1/KIBRA (PMID:30201328) and genetic suppression of a dominant-lethal TPM1 mutation in cardiac development (PMID:35243414).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 Medium

    Established that TLN2 is a distinct talin paralog rather than a talin1 variant, raising the question of isoform-specific function given its heart-enriched expression.

    Evidence Genomic assembly, EST analysis, and sequence comparison

    PMID:11527381

    Open questions at the time
    • No functional partners or activities identified
    • Expression pattern descriptive only
  2. 2005 Low

    Addressed whether talin1 and talin2 diverged functionally after duplication by showing they bind different partner sets.

    Evidence Proteomic protein-interaction profiling

    PMID:16216449

    Open questions at the time
    • Single screen without reciprocal validation or named interactors
    • No functional consequence demonstrated
  3. 2007 High

    Resolved the spatial/temporal division of labor between paralogs: talin2 is the differentiation-induced isoform of stable muscle adhesions.

    Evidence Isoform-specific antibodies, GFP imaging, and C2C12/primary myoblast differentiation time-course

    PMID:17183545

    Open questions at the time
    • Molecular mechanism of costamere targeting unknown
    • Functional necessity in muscle not yet tested by loss-of-function
  4. 2012 High

    Defined talin2's in vivo role in the heart and revealed isoform redundancy: talin2 is the dominant postnatal costameric isoform but is dispensable due to talin1 compensation, while loss of both is lethal.

    Evidence Global and cardiomyocyte-specific single and double Tln1/Tln2 knockout mice with cardiac function, histology, and β1D-integrin quantification

    PMID:23266827 PMID:28698364

    Open questions at the time
    • Mechanism of talin1 compensatory upregulation unresolved
    • Why integrin overexpression cannot rescue the double knockout unexplained
  5. 2012 Medium

    Tested whole-organism necessity of talin2 with a clean null allele, showing it is largely dispensable outside muscle stress contexts.

    Evidence Complete coding-sequence deletion knockin mouse and Tln2-null MEF adhesion/migration assays

    PMID:22925892

    Open questions at the time
    • Mild dystrophic phenotype not mechanistically explained
    • Possible talin1 compensation in MEFs not assessed
  6. 2016 High

    Identified the cellular function uniquely requiring talin2 — invadopodial traction force and matrix degradation — and traced it to its stronger β-integrin binding via Ser339.

    Evidence siRNA knockdown, traction force microscopy, invadopodia/matrix-degradation assays, and wild-type/S339C rescue

    PMID:27694340

    Open questions at the time
    • Downstream force-transduction partners at invadopodia not defined
    • In vivo metastasis relevance not tested
  7. 2016 Medium

    Linked TLN2 to a human Mendelian phenotype, providing a disease handle for the Ser339 residue.

    Evidence Exome and Sanger sequencing with four-generation co-segregation and HEK293 localization

    PMID:27223613

    Open questions at the time
    • No functional/mechanistic link between S339L and limb development
    • Localization assay single-method
  8. 2017 Medium

    Provided the structural-energetic basis for talin2's preferential β1-integrin binding, unifying the invasion and disease findings around the S339–E353 network.

    Evidence Integrin-binding affinity assays, site-directed mutagenesis, and computational molecular modeling

    PMID:28155884

    Open questions at the time
    • Structural basis inferred computationally, not by direct structure determination
    • Affinity differences not connected to cellular outputs in this study
  9. 2018 Medium

    Extended talin2 interactions beyond integrins by identifying WWC1/KIBRA as a partner that modulates tau toxicity.

    Evidence Reciprocal Co-IP in brain and HEK293, co-localization in multiple cell lines, and Drosophila tau epistasis

    PMID:30201328

    Open questions at the time
    • Mechanism of tau-toxicity modulation unknown
    • Single-lab data; binding interface undefined
  10. 2022 Medium

    Implicated talin2 as a myofilament actin-binding protein capable of genetically suppressing a dominant-lethal TPM1 mutation in cardiac development.

    Evidence CRISPR double knock-in mouse with cardiac phenotype rescue and patient iPSC-derived cardiomyocytes

    PMID:35243414

    Open questions at the time
    • Molecular mechanism of suppression unresolved
    • Residual atrial septal defect unexplained
  11. 2022 Medium

    Indicated a tumor-suppressive role in clear-cell renal carcinoma linked to Wnt/β-catenin inactivation.

    Evidence TLN2 overexpression in ccRCC cells, xenograft, cell cycle/apoptosis flow cytometry, and Wnt pathway activity assay

    PMID:35242640

    Open questions at the time
    • Pathway link not supported by direct molecular interaction
    • Apparent contrast with pro-invasive role in other cancers unreconciled
  12. 2025 High

    Established talin2 as a driver of myofibroblast differentiation and a reversible target in organ fibrosis.

    Evidence siRNA knockdown, Tln2 knockout mice, bleomycin lung and ureteral-obstruction kidney fibrosis models, α-SMA/collagen I and secretome readouts

    PMID:40410300

    Open questions at the time
    • Signaling pathway connecting talin2 to myofibroblast program undefined
    • Mechanotransduction step driving fibrotic differentiation not pinpointed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How talin2's integrin-binding adaptor activity is mechanistically converted into context-specific outputs—pro-invasive force at invadopodia versus pro-fibrotic differentiation versus tumor suppression—remains unresolved.
  • No unifying signaling mechanism across cell types
  • Force-sensing partners downstream of talin2 not mapped
  • Opposing roles in different cancers not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-397014 Muscle contraction 3 R-HSA-1474244 Extracellular matrix organization 1
Partners
Complex memberships
costamereintercalated diskinvadopodium

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TLN2 encodes a protein similar in size and sequence to talin1 throughout its length (74% identity, 86% similarity), with conserved intron/exon boundaries (except two), but gives rise to multiple transcripts with highest expression in heart, in contrast to the ubiquitously expressed single ~8-kb talin1 mRNA. Genomic database assembly, EST analysis, and sequence comparison Biochemical and biophysical research communications Medium 11527381
2005 Mammalian Talin-1 and Talin-2 bind to different protein partners as determined by proteomic analysis, indicating functional divergence following gene duplication early in the chordate lineage. Proteomic analysis (protein interaction profiling) Gene Low 16216449
2007 Talin2 expression is upregulated during striated muscle differentiation (at both mRNA and protein levels), localizes to costameres and intercalated disks in mature striated muscle (stable adhesion complexes), whereas talin1 localizes to focal adhesions in undifferentiated myoblasts. GFP-Talin2 ectopic expression in myoblasts dysregulates the actin cytoskeleton. Isoform-specific antibodies, GFP-tagging and live-cell imaging, C2C12 and primary human myoblast differentiation model, RT-PCR and western blot Cell motility and the cytoskeleton High 17183545
2012 In the adult mouse heart, Talin2 is the dominant talin isoform localizing to costameres; global deletion of Tln2 in mice caused no structural or functional cardiac changes because cardiomyocyte Talin1 became upregulated as compensation. Tln2 loss increased integrin activation but reduced β1D-integrin isoform levels by 50%. Global Tln2 knockout mouse, cardiac function assessment, western blot, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 28698364
2012 Combined loss of both CM Talin1 and Talin2 in cardiomyocytes led to cardiac dysfunction by 4 weeks with 100% mortality by 6 months, loss of β1D-integrin and other costameric proteins from cardiomyocytes, compromised membrane integrity, and dilated cardiomyopathy. Transgenic integrin overexpression could not rescue the phenotype. Cardiomyocyte-specific double knockout mice, cardiac function assessment, histology, immunofluorescence, western blot Proceedings of the National Academy of Sciences of the United States of America High 28698364
2012 Mice with complete deletion of the Tln2 coding sequence are viable and fertile with normal organ weights, displaying only a mildly dystrophic phenotype. Tln2-null mouse embryo fibroblasts show no obvious defects in cell adhesion, migration, or proliferation. Complete coding sequence deletion knockin mouse (Tln2(cd)), organ weight measurement, MEF functional assays Biochemical and biophysical research communications Medium 22925892
2012 Talin1 is the dominant talin isoform in embryonic cardiomyocytes, whereas Talin2 becomes the main isoform in postnatal cardiomyocytes, localizing to costameres. Cardiomyocyte-specific Tln1 knockout mice show normal basal cardiac structure but blunted hypertrophy, less fibrosis, and improved cardiac function after pressure overload, with strongly blunted acute ERK1/2, p38, Akt, and GSK3 signaling responses. Cardiomyocyte-specific Tln1 conditional knockout, pressure overload model, echocardiography, western blot for signaling kinases, immunofluorescence The Journal of biological chemistry High 23266827
2016 Talin2 has a much stronger binding to β-integrin tails than talin1. Talin2 localizes at invadopodia and is indispensable for traction force generation and invadopodium-mediated matrix degradation. Ablation of talin2 suppressed traction force and invadopodia formation; re-expression of wild-type talin2 but not talin1 rescued these phenotypes. Replacement of talin2 Ser339 with Cys significantly decreased its binding to β1-integrin tails to levels comparable to talin1, and talin2(S339C) could not rescue traction force or invadopodia in talin2-depleted cells. siRNA knockdown, traction force microscopy, invadopodium assay, matrix degradation assay, rescue experiments with wild-type and mutant talin2, integrin-binding assay Journal of cell science High 27694340
2017 Talin2 S339 forms a hydrogen bond with E353, which is critical for inducing key hydrogen bonds between talin2 N326 and β1-integrin R760, and between talin2 K327 and β1-integrin D759, explaining talin2's higher affinity for β1-integrin relative to talin1. Mutation of talin2 S339L (causing Fifth Finger Camptodactyly) completely disrupted binding to β-integrin tails; substitution of talin1 C336 with Ser enhanced talin1 affinity whereas S339C substitution in talin2 diminished its affinity. Integrin-binding affinity assays, site-directed mutagenesis, computational molecular modeling Scientific reports Medium 28155884
2016 Exome sequencing identified a missense variant c.1016C>T (p.S339L) in TLN2 co-segregating with Fifth Finger Camptodactyly in a four-generation Chinese Han family. Expression of wild-type and S339L mutant TLN2 in HEK293 cells showed predominant cytoplasmic localization for both. Exome sequencing, Sanger sequencing, co-segregation analysis, HEK293 overexpression with subcellular localization PloS one Medium 27223613
2018 WWC1 (KIBRA) and TLN2 co-immunoprecipitate in brain tissue and HEK293 cells, co-localize in brain tissue cells, N2a neuroblastoma, and HeLa cell lines, and co-expression of both genes modulates Tau toxicity in Drosophila eye experiments. Co-immunoprecipitation (brain tissue and HEK293), co-localization by immunofluorescence, Drosophila Tau toxicity epistasis assay Neurobiology of aging Medium 30201328
2014 miR-126-3p directly targets TLN2 by binding a responsive element within the 3'-UTR, as validated by 3'-UTR reporter assays, with an inverse correlation between miR-126-3p and TLN2 mRNA/protein levels during bovine corpus luteum development. 3'-UTR luciferase reporter assay, qRT-PCR and western blot of TLN2 during CL developmental stages Reproduction in domestic animals Medium 25244588
2022 A TLN2 variant (alongside a TPM1 variant) acts as a genetic suppressor: mouse CRISPR knock-in of both the TLN2 and TPM1 variants rescued the heart beating that is absent in Tpm1-mutant embryos (which normally die early with no heartbeat), with near-term fetuses exhibiting large atrial septal defect. This identifies TLN2 as a myofilament actin-binding protein that can suppress a dominant lethal TPM1 mutation. CRISPR knock-in mouse model, cardiac phenotype assessment, patient iPSC-derived cardiomyocytes Cell reports. Medicine Medium 35243414
2025 Knockdown of talin2 de-differentiates myofibroblasts, reducing myofibroblast-specific morphology, α-smooth muscle actin content, collagen I content, and the pro-fibrotic secretome. Tln2-/- mice are resistant to bleomycin-induced lung fibrosis and to unilateral ureteral obstruction-induced kidney fibrosis, and talin2 knockdown reverses established bleomycin-induced lung fibrosis. siRNA knockdown, Tln2 knockout mouse, bleomycin lung fibrosis model, unilateral ureteral obstruction kidney fibrosis model, α-SMA and collagen I immunofluorescence/western blot, secretome analysis Scientific reports High 40410300
2022 TLN2 overexpression inhibited ccRCC cell growth, invasion, and migration in vitro and in vivo, inhibited cell cycle progression, and promoted apoptosis. The anti-tumor function of TLN2 was mechanistically linked to inactivation of the Wnt/β-catenin signaling pathway. TLN2 overexpression in ccRCC cells, CCK-8, colony formation, transwell, wound healing assays, xenograft in vivo assay, apoptosis/cell cycle flow cytometry, Wnt/β-catenin pathway reporter/activity assay Translational andrology and urology Medium 35242640

Source papers

Stage 0 corpus · 49 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Genomic landscape of adenoid cystic carcinoma of the breast. The Journal of pathology 132 26095796
2001 Analysis of the mammalian talin2 gene TLN2. Biochemical and biophysical research communications 99 11527381
2018 The tale of two talins - two isoforms to fine-tune integrin signalling. FEBS letters 76 29723415
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
2021 Talin in mechanotransduction and mechanomemory at a glance. Journal of cell science 67 34708856
2020 The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease. Genetics in medicine : official journal of the American College of Medical Genetics 65 32037394
2007 Talin2 is induced during striated muscle differentiation and is targeted to stable adhesion complexes in mature muscle. Cell motility and the cytoskeleton 62 17183545
2017 Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America 56 28698364
2005 Gene duplication and functional divergence during evolution of the cytoskeletal linker protein talin. Gene 56 16216449
2007 Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene. Human molecular genetics 50 17584767
2020 Patient genetics is linked to chronic wound microbiome composition and healing. PLoS pathogens 48 32555671
2016 Talin2-mediated traction force drives matrix degradation and cell invasion. Journal of cell science 40 27694340
2016 Both Talin-1 and Talin-2 correlate with malignancy potential of the human hepatocellular carcinoma MHCC-97 L cell. BMC cancer 38 26822056
2012 Mice carrying a complete deletion of the talin2 coding sequence are viable and fertile. Biochemical and biophysical research communications 33 22925892
2015 Talin1 is required for cardiac Z-disk stabilization and endothelial integrity in zebrafish. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 26310270
2017 Differential Peripheral Proteomic Biosignature of Fluoxetine Response in a Mouse Model of Anxiety/Depression. Frontiers in cellular neuroscience 28 28860968
2018 Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. Neurobiology of aging 26 30201328
2014 Talin-1 correlates with reduced invasion and migration in human hepatocellular carcinoma cells. Asian Pacific journal of cancer prevention : APJCP 23 24761880
2020 Talin: A Potential Drug Target for Cancer Therapy. Current drug metabolism 22 32056520
2023 A splicing transcriptome-wide association study identifies novel altered splicing for Alzheimer's disease susceptibility. Neurobiology of disease 17 37354922
2022 Genome-Wide Association Study of Parasite Resistance to Gastrointestinal Nematodes in Corriedale Sheep. Genes 17 36140716
2024 Epithelioid Fibrous Histiocytoma Is on a Continuum With Superficial ALK -rearranged Myxoid Spindle Cell Neoplasm : A Clinicopathologic Series of 35 Cases Including Alternate RET and NTRK3 Fusions. The American journal of surgical pathology 16 39329254
2022 MicroRNA-dependent regulation of targeted mRNAs for improved muscle texture in crisp grass carp fed with broad bean. Food research international (Ottawa, Ont.) 14 35400449
2020 Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial-mesenchymal transition-related signaling pathways. Carcinogenesis 14 32710740
2023 Epigenome-wide association study identifies novel genes associated with ischemic stroke. Clinical epigenetics 12 37370144
2017 The molecular basis of talin2's high affinity toward β1-integrin. Scientific reports 12 28155884
2022 Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability. Cell reports. Medicine 10 35243414
2021 Transcriptional Changes in Regulatory T Cells From Patients With Autoimmune Polyendocrine Syndrome Type 1 Suggest Functional Impairment of Lipid Metabolism and Gut Homing. Frontiers in immunology 10 34526996
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 9 35242640
2018 Roles of Talin2 in Traction Force Generation, Tumor Metastasis and Cardiovascular Integrity. Current protein & peptide science 9 30091412
2016 Exome Sequencing of a Pedigree Reveals S339L Mutation in the TLN2 Gene as a Cause of Fifth Finger Camptodactyly. PloS one 9 27223613
2014 Characterization of miR-126-3p and its target talin2 in the bovine corpus luteum during the oestrus cycle. Reproduction in domestic animals = Zuchthygiene 9 25244588
2022 Construction and analysis of a lncRNA-miRNA-mRNA competing endogenous RNA network from inflamed and normal synovial tissues after anterior cruciate ligament and/or meniscus injuries. Frontiers in genetics 8 36324509
2020 Long Noncoding RNA Lnc-TLN2-4:1 Suppresses Gastric Cancer Metastasis and Is Associated with Patient Survival. Journal of oncology 8 32256587
2021 Molecular Features of Glioma Determined and Validated Using Combined TCGA and GTEx Data Analyses. Frontiers in oncology 7 34660294
2022 Two cases of spindle cell tumors with S100 and CD34 co-expression showing novel RAF1 fusions. Diagnostic pathology 6 36229858
2025 Epigenome-Wide Analysis Identifies Pollution-Sensitive Loci in Fibrotic Interstitial Lung Disease. American journal of respiratory and critical care medicine 5 40540633
2024 Lamc1 promotes osteogenic differentiation and inhibits adipogenic differentiation of bone marrow-derived mesenchymal stem cells. Scientific reports 5 39179716
2024 Spatial Transcriptomics Analysis: Maternal Obesity Impairs Myogenic Cell Migration and Differentiation during Embryonic Limb Development. International journal of molecular sciences 5 39273445
2023 Effects of Purine Metabolism-Related LINC01671 on Tumor Heterogeneity in Kidney Renal Clear Cell Carcinoma. Frontiers in bioscience (Landmark edition) 5 38179759
2024 Exosome-related lncRNA score: A value-based individual treatment strategy for predicting the response to immunotherapy in clear cell renal cell carcinoma. Cancer medicine 4 38808948
2024 Androgens and androgen receptor directly induce the thickening, folding, and vascularization of the seahorse abdominal dermal layer into a placenta-like structure responsible for male pregnancy via multiple signaling pathways. International journal of biological macromolecules 3 39197609
2025 Timing inaccessibility and the projection bound: Resolving Maxwell's demon for continuous biological substrates. Bio Systems 2 41187393
2022 Drug response biomarkers of Pien Tze Huang treatment for hepatic fibrosis induced by carbon tetrachloride. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan 2 35848969
2025 Identification of disulfidptosis-related genes in immunity and immunotherapy in diabetic foot ulcer. Annals of medicine and surgery (2012) 1 41675755
2026 Genetic Diversity and Selection Signal Analysis of Xinjiang Black Pig Based on Whole Genome Resequencing. Genes 0 41898827
2025 Novel genetic associations with childhood adipocytokines in Indian adolescents. Cytokine 0 40187068
2025 Inhibition of Talin2 dedifferentiates myofibroblasts and reverses lung and kidney fibrosis. Scientific reports 0 40410300
2025 Genomic insights into growth traits in German Black Pied cattle: a dual-purpose breed at risk. Animal : an international journal of animal bioscience 0 40424954

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