TLN1

TLN1 (talin-1) is a mechanosensitive focal adhesion scaffold that physically links integrins to the actin cytoskeleton and converts adhesion engagement into intracellular signaling that drives cell migration, invasion, and epithelial-mesenchymal transition (PMID:35285795, PMID:36880935). Its force-responsive architecture is tunable: a cancer-enriched alternative exon (exon 17b) inserts 17 residues into the R1-R2 linker, lowering the force threshold for opening the R1-R2 mechanosensitive switch domains, enhancing vinculin binding and altering adhesion dynamics, with this isoform switch under TGF-β/SMAD3 control (PMID:36880935). At focal adhesions TLN1 engages β1 integrin to nucleate dynamic adhesions and activate FAK-AKT signaling and EMT, and disrupting the TLN1–β1 integrin interface suppresses tumor migration and metastasis (PMID:35285795). Beyond β1 integrin, TLN1 partners with FAK in a Cdk5/TLN1/FAK axis whose scaffold (rather than catalytic) function supports invadopodia formation and trans-endothelial migration (PMID:34333365), and it associates with additional membrane partners including LAYN and NGFR to feed FAK-AKT, MAPK/ERK, and PI3K-AKT signaling in cancer contexts (PMID:39286102, PMID:42112334). TLN1 abundance is set both transcriptionally—cooperative FLI1/GATA1 regulation through an intronic FLI1-binding region is required for normal talin-1 levels in megakaryocytes, with FLI1 variants causing ~88% loss of platelet talin-1 and platelet dysfunction (PMID:39744817)—and post-translationally, via SMURF1-mediated ubiquitination and degradation that EMP1 antagonizes by competing for the TLN1 binding site (PMID:41284206).

1. 2013 Medium

   Established TLN1 as a functionally important, druggable dependency in cancer rather than a passive structural protein, by showing its loss alters therapeutic response.

   Evidence shRNA RNAi screen across breast cancer cell lines with xenograft validation showing TLN1 loss enhances docetaxel chemosensitivity in TNBC

   PMID:23479679

   Open questions at the time

   • Does not define the molecular mechanism linking TLN1 to chemoresponse
   • Restricted to TNBC; generalizability unaddressed
2. 2013 Low

   Connected TLN1 to upstream regulatory control and downstream effector signaling by placing it in a miR-9/TLN1/FAK-AKT axis controlling proliferation and invasion.

   Evidence miR-9 transfection and TLN1 siRNA with FAK/AKT Western blots and migration/invasion assays in ovarian serous carcinoma

   PMID:23722670

   Open questions at the time

   • Direct miR-9 targeting of the TLN1 transcript not rigorously demonstrated in the abstract
   • Single cancer type, single lab
3. 2021 Medium

   Separated TLN1's scaffold function from phosphorylation-dependent signaling, showing the structural role in a Cdk5/TLN1/FAK axis is what enables invadopodia and vascular breaching.

   Evidence 3D microfluidic vascularized models with siRNA knockdown of TLN1 and FAK, chemical FAK inhibition, and in vivo lung colonization

   PMID:34333365

   Open questions at the time

   • Molecular detail of how Cdk5 couples to the TLN1/FAK complex unresolved
   • Direct TLN1–FAK binding interface not mapped
4. 2022 Medium

   Defined the TLN1–β1 integrin interface as a targetable node driving adhesion dynamics and metastasis, moving from correlation to a chemically tractable mechanism.

   Evidence siRNA knockdown, computational small-molecule screen against the TLN1–β1 binding interface (C67399), focal adhesion imaging, and TNBC xenograft metastasis

   PMID:35285795

   Open questions at the time

   • Specificity of C67399 for the TLN1–integrin interface in vivo not fully characterized
   • Single lab
5. 2023 High

   Revealed how TLN1 mechanosensitivity is tuned in disease via a cancer-enriched alternative exon that lowers the force threshold for switch-domain opening, linking splicing to adhesion mechanics.

   Evidence Splicing analysis, in vitro force-extension and vinculin binding assays, live adhesion/motility imaging, and TGF-β/SMAD3 pathway perturbation

   PMID:36880935

   Open questions at the time

   • In vivo prevalence and functional consequence of exon 17b across tumor types not established
   • Mechanism by which SMAD3 directs the splice choice not detailed
6. 2023 Low

   Extended TLN1 function into vascular endothelial protection by placing it upstream of ITGA5, broadening its role beyond migration.

   Evidence Overexpression/knockdown of TLN1 and ITGA5 in cardiac microvascular endothelial cells under ox-LDL injury with functional rescue

   PMID:37144848

   Open questions at the time

   • No direct TLN1–ITGA5 binding assay
   • Mechanism by which TLN1 raises ITGA5 expression unknown
7. 2023 Low

   Catalogued a novel post-translational modification (lysine malonylation) on TLN1, raising a regulatory layer relevant to platelet activation signaling.

   Evidence Affinity enrichment and LC-MS/MS malonylome profiling of PBMCs from ESRD patients

   PMID:37833721

   Open questions at the time

   • No functional validation that malonylation alters TLN1 activity
   • Single proteomic descriptive study
8. 2024 Medium

   Identified LAYN as a direct TLN1 partner within a transcription-to-adhesion axis (CREB1-LAYN-TLN1-β1 integrin) driving cholangiocarcinoma metastasis via MAPK/ERK signaling.

   Evidence Co-IP for LAYN–TLN1, ChIP for CREB1, siRNA, Western blot, Transwell assays, and nude mouse metastasis model

   PMID:39286102

   Open questions at the time

   • Reciprocal/structural mapping of the LAYN–TLN1 interface absent
   • Single lab and cancer type
9. 2025 Medium

   Defined transcriptional control of TLN1 abundance, showing cooperative FLI1/GATA1 regulation is required for talin-1 expression in megakaryocytes and links FLI1 variants to platelet disease.

   Evidence scRNA-seq of patient megakaryocytes, ChIP-seq, luciferase reporters, FLI1 variant transcription assays, and Western blot of patient platelets

   PMID:39744817

   Open questions at the time

   • Whether reduced talin-1 alone accounts for the platelet phenotype not isolated
   • GATA1 contribution to the intronic element not separately dissected
10. 2025 Medium

    Established post-translational control of TLN1 stability through SMURF1-mediated ubiquitination and its antagonism by EMP1, linking TLN1 turnover to hepatic stellate cell activation.

    Evidence Rodent MASLD-IRI models, EMP1 silencing, Co-IP mapping EMP1–SMURF1–TLN1 competition, and Western blot for ubiquitination and FAK phosphorylation

    PMID:41284206

    Open questions at the time

    • SMURF1 ubiquitination site(s) on TLN1 not mapped
    • Single lab; competitive binding inferred from Co-IP
11. 2026 Medium

    Added NGFR as a direct TLN1 partner in castration-resistant prostate cancer, with epistasis showing TLN1 acts through NGFR to drive proliferation, invasion, and EMT via MAPK and PI3K-AKT.

    Evidence Mass spectrometry, Co-IP, molecular docking, transcriptome sequencing, siRNA, xenograft, and functional assays with NGFR rescue

    PMID:42112334

    Open questions at the time

    • Structural basis of the TLN1–NGFR interaction not resolved beyond docking
    • Single lab and tumor context

• How the distinct regulatory layers on TLN1 — splice-isoform mechanotuning, transcriptional control, ubiquitin-dependent turnover, and malonylation — are integrated to set adhesion behavior in a given cell type remains unresolved.
• No unified model coupling TLN1 abundance, modification state, and isoform identity to adhesion output
• Cross-talk among SMURF1/EMP1, FLI1/GATA1, and SMAD3 inputs not tested together