Affinage

DLC1

Rho GTPase-activating protein 7 · UniProt Q96QB1

Length
1528 aa
Mass
170.6 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLC1 is a multidomain focal adhesion protein that functions as a tumor suppressor by acting as a GTPase-activating protein (GAP) for the Rho subfamily, with strong activity toward RhoA, RhoB, and RhoC and only limited activity toward Cdc42 (PMID:14633684, PMID:17932950). Through this RhoGAP activity it lowers RhoA-GTP, disassembles actin stress fibers and focal adhesions, and suppresses downstream Rho/ROCK/MLC2 signaling, and these effects require its catalytic arginine finger (PMID:18648664, PMID:18519636). DLC1 RhoGAP activity is held in a closed, autoinhibited conformation in which an N-terminal region (including the SAM domain) folds back onto the RhoGAP domain (PMID:18786931, PMID:25452387); this autoinhibition is relieved by CDK5 phosphorylation, by binding of tensin family C2/actin-binding domains and PTEN, by PI(4,5)P2 engagement of a polybasic region, and by PKA-driven Ser549 phosphorylation that promotes activating dimerization, whereas AKT phosphorylation, 14-3-3 binding, and the p120RasGAP SH3 domain hold or convert DLC1 into the inactive state (PMID:19066281, PMID:19151751, PMID:19710422, PMID:22307599, PMID:23511482, PMID:25452387, PMID:29114068, PMID:31806702, PMID:35970859). DLC1 is recruited to focal adhesions through an LD-like motif that binds talin and FAK and through a FAT domain, with talin R8 unfolding under mechanical force acting as a force-sensitive scaffold for downstream RhoA signaling (PMID:21969587, PMID:27265849, PMID:30028837, PMID:19170769). Beyond catalysis, DLC1 also acts through RhoGAP-independent routes — START-domain binding to caveolin-1, SAM-domain binding to EF1A1, displacement of S100A10 to promote its degradation, and complex formation with α-catenin to stabilize adherens junctions (PMID:19158340, PMID:21372205, PMID:22473989, PMID:22693251). Its expression is controlled by YAP/TAZ-TEAD transcription and its protein level by CRL4A-DDB1-FBXW5-mediated ubiquitin-proteasomal degradation (PMID:24082123, PMID:31964713). DLC1 is essential for development, as its loss is embryonic lethal in mice with defective actin organization, and its loss in cancer cells drives RhoA-dependent metastasis, including TGF-β/SMAD3/PTHLH-driven osteolytic bone metastasis (PMID:24590291, PMID:15710412, PMID:20199662).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Established the core molecular identity of DLC1 as a Rho-family GAP, defining the enzymatic activity around which all later mechanism was built.

    Evidence In vitro GAP activity assay showing specificity for RhoA and Cdc42

    PMID:14633684

    Open questions at the time
    • Cellular substrate selectivity not yet resolved
    • No information on regulation of the activity
  2. 2008 High

    Resolved the substrate spectrum and revealed that flanking domains autoinhibit the catalytic domain, reframing DLC1 as a conformationally regulated enzyme.

    Evidence In vitro GAP assays comparing full-length versus isolated RhoGAP domain plus RhoA biosensor imaging; SAM-domain truncation/missense mutagenesis

    PMID:17932950 PMID:18786931

    Open questions at the time
    • Trigger that relieves SAM autoinhibition not identified
    • Mechanism of focal adhesion recruitment independent of SAM/START not defined
  3. 2008 High

    Connected DLC1 catalytic activity to a defined cytoskeletal signaling output, showing it suppresses the Rho/ROCK/MLC2 axis in a GAP-dependent manner.

    Evidence Immunofluorescence, western blot, RhoGAP-dead (K714E) mutant, and dominant-active ROCK epistasis in hepatocellular carcinoma cells

    PMID:18648664

    Open questions at the time
    • Did not address RhoGAP-independent contributions
    • In vivo relevance not tested in this study
  4. 2009 High

    Identified multiple inputs that tune DLC1 activity and localization — negative (14-3-3, p120RasGAP SH3) and positive (PI(4,5)P2, tensin binding) — establishing DLC1 as a signaling hub.

    Evidence Co-IP, in vitro GAP assays with purified proteins and PI(4,5)P2 liposomes, mutagenesis of binding motifs, RhoA pulldowns

    PMID:19066281 PMID:19151751 PMID:19440389 PMID:19710422 PMID:19826001

    Open questions at the time
    • How these regulators are integrated in time and space unresolved
    • Some interactions characterized in single labs without reciprocal validation
  5. 2009 High

    Demonstrated that DLC1 suppresses migration through RhoGAP-independent protein interactions, beginning the dissection of catalytic versus scaffolding functions.

    Evidence NMR structure of the SAM domain, mass spectrometry identification of EF1A1, mutagenesis of a hydrophobic patch, and migration assays

    PMID:19158340

    Open questions at the time
    • Quantitative contribution of EF1A1 axis versus RhoGAP activity unclear
    • Mechanism linking EF1A1 redistribution to migration not fully defined
  6. 2011 High

    Expanded the RhoGAP-independent tumor suppressor repertoire by showing DLC1 destabilizes S100A10 to limit plasminogen activation.

    Evidence Reciprocal co-IP, Annexin 2 competition assay, RhoGAP-independence controls, and invasion/migration assays

    PMID:21372205

    Open questions at the time
    • Identity of the ubiquitin ligase for S100A10 not established
    • In vivo relevance of this axis not demonstrated
  7. 2011 High

    Defined the structural basis of DLC1 focal adhesion targeting through an LD-like motif binding talin and FAK, linking localization to tumor suppression.

    Evidence Co-IP, mutagenesis, focal adhesion imaging, and growth/colony-formation assays

    PMID:21969587

    Open questions at the time
    • Functional separation of talin versus FAK binding not fully resolved
    • How localization potentiates GAP output mechanistically unclear
  8. 2012 High

    Established additional RhoGAP-independent (caveolin-1, α-catenin) and activating (tensin3) mechanisms, clarifying how distinct domains drive distinct anti-tumor outputs.

    Evidence Reciprocal co-IP with domain mapping, in vitro RhoGAP assays, FRAP, active Rho pulldown, and functional growth/junction assays

    PMID:22307599 PMID:22473989 PMID:22693251

    Open questions at the time
    • Relative weighting of GAP-dependent and GAP-independent mechanisms in tumors unclear
    • Whether these complexes coexist on the same DLC1 molecule unknown
  9. 2013 High

    Defined opposing post-translational controls on DLC1 — activating PKA phosphorylation/dimerization and inactivating CRL4A-FBXW5 degradation — explaining DLC1 loss in cancer.

    Evidence Kinase assay, dimerization co-IP, ubiquitination assay, siRNA epistasis, RhoA pulldown, and tumor suppression assays

    PMID:23376848 PMID:23511482 PMID:24082123

    Open questions at the time
    • Crosstalk between phospho-activation and ubiquitin-driven turnover not integrated
    • Upstream signals controlling FBXW5 recruitment unknown
  10. 2014 High

    Identified the kinase switches (CDK5 activating, AKT inhibiting) that toggle DLC1 between open dimeric active and closed monomeric inactive states, and linked DLC1 loss to bone metastasis.

    Evidence Kinase assays, autoinhibition co-IP, mutagenesis, focal adhesion imaging, and in vivo metastasis model with ROCK inhibition

    PMID:24590291 PMID:25452387 PMID:29114068

    Open questions at the time
    • How CDK5 and AKT phosphorylation are coordinated in vivo unresolved
    • Therapeutic window of AKT inhibition in DLC1-positive tumors not defined here
  11. 2016 High

    Provided atomic-resolution definition of the talin R8–DLC1 LD interaction, anchoring the recruitment model structurally.

    Evidence X-ray crystallography of talin R8–DLC1 LD complex with interface mutagenesis validated in cells

    PMID:27265849

    Open questions at the time
    • Competition with paxillin LD motifs for the same R8 surface in cells not quantified
    • Dynamics of binding under load not addressed by static structure
  12. 2018 High

    Established DLC1 as part of a mechanotransduction circuit in which force-induced talin R8 unfolding gates DLC1 signaling, and revealed a GAP-independent role in endothelial ICAM-1 adhesome assembly.

    Evidence Force-resistant talin mutant with AFM and traction force microscopy; ICAM-1 clustering, co-IP, and leukocyte adhesion assays

    PMID:30028837 PMID:30231995

    Open questions at the time
    • How unfolding-dependent recruitment is converted to local RhoA inactivation mechanistically unclear
    • ICAM-1 adhesome role characterized in a single lab
  13. 2019 High

    Refined the activation mechanism by mapping SAM-domain engagement of tensin3 and PTEN C2 domains and demonstrating peptide-based reactivation of DLC1.

    Evidence Co-IP, in vitro RhoGAP assays, and cell-penetrating C2-derived peptide functional assays

    PMID:31806702

    Open questions at the time
    • Structural basis of SAM–C2 binding not resolved
    • Specificity and off-target effects of the cyclic peptide not fully characterized
  14. 2020 High

    Placed DLC1 within mechanosensitive transcriptional control by identifying it as a direct YAP/TAZ-TEAD target governing endothelial migration and angiogenic sprouting.

    Evidence ChIP of YAP/TAZ-TEAD on the DLC1 promoter, siRNA depletion with rescue, traction force microscopy, and sprouting assays

    PMID:31964713

    Open questions at the time
    • Feedback between DLC1-controlled mechanics and YAP/TAZ activity not resolved
    • Generalizability beyond endothelial context untested in this study
  15. 2022 High

    Provided the structural mechanism for p120RasGAP SH3 inhibition, showing it occludes the RhoA-binding site and catalytic arginine finger.

    Evidence Co-crystal structure of p120RasGAP SH3–DLC1 RhoGAP with interface mutagenesis and in vitro activity assays

    PMID:35970859

    Open questions at the time
    • Cellular conditions selecting SH3-bound versus active state unknown
    • Interplay with other regulators at the same surface not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many competing activating and inhibitory inputs are integrated spatiotemporally on a single DLC1 molecule to set local RhoA activity in a given cellular context remains unresolved.
  • No unified model reconciling kinase, lipid, scaffold, and ubiquitin inputs
  • Limited structural data on full-length autoinhibited DLC1
  • Relative in vivo contribution of GAP-dependent versus GAP-independent functions across tissues unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
CAV1CTNNA1PTENPTK2RASA1S100A10TLN1TNS3
Complex memberships
ICAM-1 adhesomeadherens junction (E-cadherin/β-catenin/α-catenin)focal adhesion

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 DLC1 protein functions as a GTPase-activating protein (GAP) specific for RhoA and Cdc42, as established by in vitro GTPase activating protein activity assay. In vitro GAP activity assay Cancer research High 14633684
2008 Full-length DLC1 exhibits strong GAP activity for RhoA, RhoB, and RhoC but only very limited activity for Cdc42 in vitro; in contrast, the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for RhoA, RhoB, RhoC, and Cdc42, suggesting the flanking domains impose autoinhibition. DLC1 reduces RhoA activity at the leading edge of cellular protrusions, and its anti-tumor activity involves both RhoGAP-dependent and RhoGAP-independent mechanisms. Unlike rat p122RhoGAP, human DLC1 was not capable of activating phospholipase C-delta1. In vitro GAP activity assay, RhoA biosensor live imaging, cell-based assays Molecular carcinogenesis High 17932950
2008 DLC1 negatively regulates the Rho/ROCK/MLC2 pathway in hepatocellular carcinoma. Ectopic DLC1 expression abrogates Rho/ROCK-mediated cytoskeletal reorganization (stress fibers, focal adhesions) and downregulates cortical phosphorylation of myosin light chain 2 (MLC2) and MYPT1 phosphorylation at Thr853. A RhoGAP-deficient mutant (K714E) abolishes these inhibitory effects, confirming RhoGAP-dependency. Dominant-active ROCK rescues cells from DLC1-induced cytoskeletal collapse. Immunofluorescence, western blot, dominant-active ROCK epistasis, RhoGAP-dead mutant PloS one High 18648664
2008 The SAM domain of DLC1 functions as an autoinhibitory domain of intrinsic RhoGAP activity. The SAM and START domains are dispensable for DLC1 association with focal adhesions. A dominant-negative N-terminal fragment displaces endogenous DLC1 from focal adhesions and profoundly inhibits cell migration. Structure-function analysis with truncation and missense mutants, cell morphology and migration assays The Journal of biological chemistry High 18786931
2008 DLC1 interacts with 14-3-3 adaptor proteins via phosphoserine recognition motifs involving Ser327 and Ser431. Phorbol-ester-induced activation of PKC/PKD stimulates this association. Binding to 14-3-3 inhibits DLC1 GAP activity, facilitates RhoA signaling, and blocks DLC1 nucleocytoplasmic shuttling by masking a nuclear localization sequence. Co-immunoprecipitation, in vitro GAP assay, site-directed mutagenesis, subcellular fractionation/imaging Journal of cell science High 19066281
2009 p120Ras-GAP (RASA1) interacts with DLC1 and colocalizes in focal adhesions. The Ras-GAP SH3 domain binds the DLC1 RhoGAP domain and inhibits DLC1 RhoGAP activity in vitro. Overexpression of Ras-GAP impairs DLC1 growth-suppressing activity and increases RhoA activity in vivo. Co-immunoprecipitation, in vitro GAP assay with purified proteins, cell growth assay, active RhoA pulldown Oncogene High 19151751
2009 The SAM domain of DLC1 binds eukaryotic elongation factor 1A1 (EF1A1) but not the SAM domain of DLC2. The solution structure of DLC1 SAM reveals a monomeric fold with four parallel helices. A hydrophobic patch (F38, L39, F40) is required for EF1A1 interaction. SAM-EF1A1 interaction facilitates EF1A1 distribution to membrane periphery upon growth factor stimulation and contributes to DLC1-mediated suppression of cell migration independent of the RhoGAP domain. Protein precipitation, mass spectrometry, NMR structure, mutagenesis, cell migration assay Journal of cell science High 19158340
2009 DLC1 activation requires binding to phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] through a polybasic region (PBR) adjacent to the RhoGAP domain. PI(4,5)P2-containing membranes stimulate DLC1 GAP activity in vitro. A PBR-deficient DLC1 mutant is severely compromised in suppressing cell spreading, directed migration, and proliferation. Lipid-binding assay, in vitro GAP activity assay with PI(4,5)P2 liposomes, mutagenesis, cell-based assays Molecular biology of the cell High 19710422
2009 Tensin1 requires its SH2 domain (R1488) to bind DLC1; tensin1 F302A mutation (abrogating PP1alpha binding) also reduces DLC1 association, linking PP1alpha and DLC1 to tensin1 signaling. DLC1 binding via tensin mediates Rho regulation, but PP1alpha has additional DLC1-independent effects on migration and invasion. Co-immunoprecipitation, mutagenesis, cell migration and invasion assays, MLC20 phosphorylation western blot The Journal of biological chemistry Medium 19826001
2009 Tensin2 binds DLC1 via its PTB domain at a novel binding site (residues 375–385 of DLC1). Deletion of this PTB-binding site partially reduces DLC1 RhoGAP activity and attenuates growth-suppressive activity without affecting focal adhesion localization or tensin1/cten interactions. Co-immunoprecipitation, deletion mutagenesis, RhoGAP activity assay, growth suppression assay PloS one Medium 19440389
2010 Tensin2 knockdown significantly reduces the ability of human foreskin fibroblasts to contract 3D collagen gels, associated with reduced Rho activity; this inhibition is reversed by depletion of DLC1, placing DLC1 downstream of tensin2 in regulating Rho-mediated actomyosin contraction and collagen remodeling. siRNA knockdown, 3D collagen gel contraction assay, RhoA activity pulldown, epistasis by double knockdown Journal of cellular biochemistry Medium 20069572
2011 DLC1 binds S100A10 (p11) in the cell cytoplasm; the interaction is mediated by central sequences in DLC1 and the C-terminus of S100A10. DLC1 competes with Annexin 2 for S100A10 binding, displacing S100A10 from Annexin 2 and making it accessible to ubiquitin-dependent degradation, thereby decreasing S100A10 steady-state levels and attenuating plasminogen activation. This mechanism inhibits cell migration, invasion, and anchorage-independent growth independently of DLC1 RhoGAP activity. Co-immunoprecipitation, colocalization imaging, competition assay, RhoGAP activity assay, cell invasion/migration assays Cancer research High 21372205
2011 DLC1 contains an 8-aa LD-like motif (residues 469LDDILYHV476) that is necessary for binding to talin and FAK. This motif is required for DLC1 localization to focal adhesions and for full tumor suppressor activity. FAK binding is independent of talin and vice versa. Mutants deficient in talin/FAK binding have impaired tumor suppressor activity despite retained ability to negatively regulate overall Rho-GTP. Co-immunoprecipitation, mutagenesis, focal adhesion localization imaging, bioassays (growth inhibition, colony formation) Proceedings of the National Academy of Sciences of the United States of America High 21969587
2012 DLC1 forms a complex with α-catenin; binding is mediated by DLC1 N-terminal residues 340–435 and α-catenin residues 117–161. DLC1-α-catenin colocalize in cytosol and plasma membrane, where they associate with E-cadherin and β-catenin. DLC1-α-catenin complex reduces RhoA-GTP at the plasma membrane, increases E-cadherin mobility, and stabilizes adherens junctions. DLC1 GAP activity is required for α-catenin accumulation at the plasma membrane. Co-immunoprecipitation, mutagenesis, colocalization immunofluorescence, active Rho pulldown, E-cadherin FRAP, cell-based functional assays Molecular and cellular biology High 22473989
2012 Tensin3 activates DLC1 RhoGAP activity by binding DLC1 through its actin-binding domain, thereby releasing an autoinhibitory interaction between the SAM and RhoGAP domains of DLC1. Cten (C-terminal tensin-like protein), which lacks the actin-binding domain, does not activate DLC1. Tensin3 depletion augments actin stress fibers and focal adhesions and enhances cell motility via RhoA/ROCK signaling. Co-immunoprecipitation, in vitro RhoGAP activity assay, siRNA knockdown, actin/focal adhesion imaging, ROCK inhibitor rescue Proceedings of the National Academy of Sciences of the United States of America High 22307599
2012 DLC1 forms a complex with caveolin-1 (CAV-1); the interaction is mapped to the DLC1 START domain. Mutation of the START domain disrupts interaction and colocalization with CAV-1 and abolishes suppression of neoplastic growth, even though RhoA regulation is retained. This defines a RhoGAP-independent tumor suppressor mechanism mediated by the START domain-CAV-1 interaction. Co-immunoprecipitation, domain mutagenesis, colocalization imaging, anchorage-independent growth assay, active RhoA pulldown Cancer research High 22693251
2013 DLC1 is ubiquitinated and degraded by the CRL4A (cullin 4A-RING ubiquitin ligase) complex via DDB1 and FBXW5 substrate receptor, providing a post-translational mechanism for DLC1 loss in NSCLC. siRNA suppression of cullin 4A, DDB1, or FBXW5 restores DLC1 protein, reduces RhoA-GTP, and causes DLC1-dependent decreases in NSCLC proliferation. siRNA knockdown, co-immunoprecipitation (ubiquitin ligase complex), ubiquitination assay, active RhoA pulldown, cell proliferation assay Proceedings of the National Academy of Sciences of the United States of America High 24082123
2013 PKA phosphorylates DLC1 at Ser549, enhancing its RhoGAP activity and promoting its tumor suppressor functions (suppression of hepatoma cell growth, motility, and metastasis). Ser549 phosphorylation induces dimerization of DLC1, and inducible dimerization alone can rescue tumor suppressive and RhoGAP activities of a Ser549-deletion DLC1 mutant. Site-directed mutagenesis, kinase assay, co-immunoprecipitation (dimerization), RhoGAP activity assay, in vitro and in vivo tumor suppression assays Nature communications High 23511482
2013 DLC1 expression in metastatic prostate carcinoma cells induces E-cadherin expression at the mRNA level through suppression of RhoA-GTP and RhoC-GTP via its RhoGAP function. Rho/ROCK inhibitors mimic this effect. Knockdown of RhoC (more than RhoA) increases E-cadherin. Constitutively active RhoA(V14) and RhoC(V14) could not be reversed by DLC1, confirming epistasis. Gene expression (RT-PCR/western blot), ROCK inhibitors, shRNA, constitutively active Rho mutants (epistasis), cell invasion assay Oncogene High 23376848
2014 CDK5 is a major regulator of DLC1. CDK5 phosphorylates four serines in DLC1 N-terminal to the RhoGAP domain. When unphosphorylated, this N-terminal region acts as an autoinhibitory domain that binds the RhoGAP domain and places DLC1 in a closed, inactive conformation. CDK5 phosphorylation reduces this autoinhibitory binding and coordinately activates DLC1 localization to focal adhesions, RhoGAP activity, and ability to bind tensin and talin. Kinase assay (CDK5 phosphorylation), mutagenesis, co-immunoprecipitation (autoinhibitory domain interaction), focal adhesion localization imaging, RhoGAP activity assay, tensin/talin binding assay The Journal of cell biology High 25452387
2014 Loss of DLC1 activates Rho-ROCK signaling, which mediates SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation and osteolytic bone metastasis. Pharmacological inhibition of Rho-ROCK reduces PTHLH production and breast cancer bone metastasis in vitro and in vivo. siRNA knockdown, ROCK inhibitor, phosphorylation analysis, PTHLH expression assay, in vivo mouse metastasis model The Journal of clinical investigation High 24590291
2016 The crystal structure of the talin R8 domain bound to the DLC1 LD motif reveals that the DLC1 LD helix binds the four-helix bundle of talin R8 in a canonical triple-helix arrangement. The same R8 surface interacts with paxillin LD1 and LD2 motifs. Key charged residues stabilize R8-LD interactions, and mutations at this interface disrupt DLC1 binding and function in cells. X-ray crystallography, mutagenesis, in vitro binding assay, cell-based functional assays Structure High 27265849
2017 Multiple RTK ligands increase RhoA-GTP in cells via AKT activation. AKT phosphorylates three serines (S298, S329, S567) in DLC1 N-terminal to the RhoGAP domain, inducing strong binding of that N-terminal region to the RhoGAP domain and converting DLC1 from an open, active dimer to a closed, inactive monomer. This reduces RhoA-GTP hydrolysis, binding of other DLC1 ligands, colocalization with focal adhesions, and tumor suppressor activity. AKT inhibition has potent antitumor activity specifically in DLC1-positive cancers. Kinase assay, mutagenesis, co-immunoprecipitation, active RhoA pulldown, focal adhesion localization imaging, in vivo tumor model, isogenic DLC1+/- cell lines The Journal of cell biology High 29114068
2018 Talin R8 domain unfolding by mechanical force is required for DLC1 downstream signaling. Using a talin mutant resistant to force-induced R8 unfolding, DLC1 signaling (RhoA regulation) and cell mechanics are dependent on talin unfolding status, defining a mechanotransduction mechanism where talin acts as a force-sensitive scaffold for DLC1. Protein engineering (force-resistant talin mutant), atomic force microscopy, traction force microscopy, biophysical assays PLoS biology High 30028837
2018 DLC1 depletion in endothelial cells on stiff substrates reduces cell stiffness and impairs ICAM-1 adhesome formation by preventing recruitment of filamin B, α-actinin-4, and cortactin to clustered ICAM-1, thereby impairing leukocyte spreading. DLC1 overexpression rescues ICAM-1 adhesome stabilization. This function is independent of the DLC1 GAP domain. siRNA knockdown, DLC1 overexpression rescue, ICAM-1 clustering assay, co-immunoprecipitation, stiffness measurement (AFM), leukocyte adhesion assay Cell reports Medium 30231995
2019 The DLC1 SAM domain binds to specific peptide motifs within the C2 domains of tensin3 and PTEN. This SAM-C2 interaction mediates DLC1 activation. Peptides containing the C2 binding motifs block the C2-SAM interaction, promote DLC1 RhoGAP activity, decrease RhoA activation, and reduce tumor cell growth and migration. A cyclic version of the TNS3 C2-derived peptide enters cancer cells and effectively inhibits migration. Co-immunoprecipitation, in vitro RhoGAP activity assay, cell-penetrating peptide functional assays, soft agar growth, migration assay The Journal of biological chemistry High 31806702
2020 DLC1 is a direct transcriptional target of the activated YAP/TAZ-TEAD complex. Substrate stiffening and VEGF stimulate DLC1 expression in endothelial cells in a YAP/TAZ-dependent manner. DLC1 limits F-actin fiber formation, integrin-based focal adhesion lifetime, and traction forces. DLC1 depletion impairs endothelial cell polarization in directed collective migration and inhibits angiogenic sprouting; ectopic DLC1 expression rescues migration and sprouting in YAP-depleted cells. Chromatin immunoprecipitation (YAP/TAZ-TEAD binding to DLC1 promoter), siRNA depletion, rescue overexpression, live imaging of migration, sprouting assay, traction force microscopy Journal of cell science High 31964713
2017 DLC1 localizes asymmetrically to the cytoplasm at the cell front in avian trunk neural crest cells. This asymmetric localization depends on association of DLC1 with NEDD9. Asymmetric DLC1 creates differential RhoA activity (high at rear, fluctuating at front), determining polarized morphology and directional migration. SOX10 regulates DLC1 expression; SOX9 regulates NEDD9. RhoA FRET biosensor in vivo and in vitro, DLC1 overexpression/knockdown, NEDD9 co-immunoprecipitation and knockdown, in vivo neural crest imaging Nature communications High 29084958
2022 The co-crystal structure of the p120RasGAP SH3 domain bound directly to DLC1 RhoGAP shows the SH3 domain binds at a site partially overlapping the RhoA binding site and impinging on the catalytic arginine finger, directly inhibiting GAP activity. Mutations at this interface biochemically relieve SH3-mediated inhibition of DLC1 RhoGAP activity. X-ray co-crystallography, in vitro RhoGAP activity assay, mutagenesis Nature communications High 35970859
2005 DLC1 knockout mice (DLC1-/-, Arhgap7) are embryonic lethal by day 10.5 post coitum, with defects in neural tube, brain, heart, and placenta. Cultured DLC1-deficient embryonic fibroblasts display alterations in actin filament organization and focal adhesions, demonstrating an essential developmental role in cytoskeletal regulation. Homologous recombination gene knockout, histological analysis, immunofluorescence (actin/focal adhesions) in primary fibroblasts FEBS letters High 15710412 20199662
2017 Dlc1 is required for white and brown adipocyte differentiation. Dlc1 knockdown reduces lipid droplet formation and fat marker gene expression in white adipocytes, and reduces brown fat-specific gene expression and mitochondrial respiration in brown adipocytes. Dlc1-/- MEFs cannot differentiate into adipocytes, but this is rescued by ROCK and F-actin inhibitors, implicating the Rho pathway. PPARγ binds the Dlc1 promoter to regulate its expression during adipogenesis. siRNA knockdown, Dlc1-/- MEFs, ROCK/F-actin inhibitor rescue, ChIP (PPARγ binding), adipocyte differentiation assays, mitochondrial respiration measurement PloS one High 28358928
2020 DLC1 negatively regulates TCTP (translationally controlled tumor protein) in a RhoGAP-independent manner. DLC1 and TCTP colocalize at focal adhesions and form a complex. Depletion of DLC1 increases TCTP expression; transfection with either WT or GAP-dead DLC1 (R718A) decreases TCTP levels. DLC1/TCTP interaction modulates Cdc42-JNK/NF-κB and N-WASP signaling to regulate cancer cell migration. Co-immunoprecipitation, colocalization imaging, GAP-dead mutant, siRNA knockdown, western blot, cell migration assay Food & function Medium 33150340
2004 p122 (rat DLC1 ortholog) localizes to caveolin-enriched membrane domains (caveolae) via its C-terminal GAP domain-containing region. Expression of p122/RhoGAP causes internalization of caveolin-1, and the GAP domain is responsible for its patchy plasma membrane distribution. This localization and function are cholesterol-dependent. EGFP tagging and live/fixed cell imaging, sucrose density gradient fractionation, immunostaining, cholesterol depletion Genes to cells Medium 14723705
2008 Focal adhesion localization of DLC1 (START-GAP1) is mediated by residues 265–459 ('FAT domain'). Expression of the FAT domain alone as a dominant-negative disrupts endogenous DLC1 localization, reduces cell migration, and impairs cell spreading. Focal adhesion localization is required for DLC1-mediated cell morphology changes. Immunofluorescence, deletion mutagenesis, dominant-negative expression, cell migration assay Genes to cells Medium 19170769
2007 Restoration of DLC1 expression in DLC1-null hepatocellular carcinoma cells causes inhibition of cell proliferation, disassembly of stress fibers, membrane protrusion, inhibition of cell migration, and dephosphorylation of focal adhesion proteins FAK, p130Cas, and paxillin. Adenoviral DLC1 transduction, cell proliferation assay, immunofluorescence, western blot of phospho-focal adhesion proteins, migration assay Biochemical and biophysical research communications Medium 17292327
2010 DLC1 silencing in non-malignant prostate epithelial cells does not promote more aggressive tumor phenotypes but promotes pro-angiogenic responses through VEGF upregulation. DLC1 loss leads to accumulation and nuclear localization of HIF-1α. VEGF modulation by DLC1 loss is dependent on EGFR-MEK-HIF-1α signaling, not RhoA. shRNA knockdown, VEGF ELISA, HIF-1α immunofluorescence/fractionation, EGFR/MEK inhibitors, RhoA inhibitor comparison Cancer research Medium 20861185
2011 Silencing of DLC1 in normal prostate epithelial cells reduces (not increases) cell migration due to upregulation of plasminogen activator inhibitor 1 (PAI-1). PAI-1 silencing rescues the migration defect. DLC1-K714E (GAP-inactive mutant) cannot decrease PAI-1 or rescue migration, indicating GAP-dependent PAI-1 regulation. DLC1-Y442F (tensin-binding defective) suppresses PAI-1 but does not restore migration, defining two independent DLC1 functions in normal cells. shRNA knockdown, DLC1 mutant re-expression, PAI-1 western blot, Transwell and wound-healing migration assays, PAI-1 siRNA rescue Molecular cancer research Medium 22064653
2016 Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9) in multiprotein complexes. Dlc1 overexpression increases phosphorylation of Myh9 and activates Rac1 GTPase, contributing to induced cell elongation morphology. Mass spectrometry interactome, co-immunoprecipitation validation, western blot for Myh9 phosphorylation, Rac1 activity pulldown Biology open Medium 26977077
2007 DLC1 protein undergoes nuclear translocation in a fraction of cells; this process requires the RhoGAP domain and a bipartite nuclear localization sequence. Nuclear DLC1 functions as an inducer of caspase-3-dependent apoptosis, while cytoplasmic DLC1 inhibits tumor cell proliferation and migration. DLC1 mutant analysis, immunofluorescence/subcellular fractionation, caspase-3 assay, cell migration/proliferation assays Experimental cell research Medium 17888903
2008 DLC1 tumor suppressor protein, when reintroduced into hepatoma cells with low DLC1 levels, reduces levels of GTP-bound RhoA; enforced expression of constitutively active RhoA mimics DLC1 loss in promoting hepatocellular carcinogenesis; down-regulation of RhoA selectively inhibits tumor growth of DLC1-disabled hepatoma cells, establishing DLC1 acts through the RhoA pathway in vivo. RNAi knockdown, constitutively active RhoA expression, shRNA RhoA knockdown, in vivo mouse hepatocellular carcinoma model Genes & development High 18519636

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer research 166 14633684
2007 DLC-1:a Rho GTPase-activating protein and tumour suppressor. Journal of cellular and molecular medicine 162 17979893
2008 DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. Genes & development 160 18519636
2005 The RhoGAP protein DLC-1 functions as a metastasis suppressor in breast cancer cells. Cancer research 131 16024604
2003 DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. Oncogene 130 12545165
2004 DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. Oncogene 129 14661059
2008 DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms. Molecular carcinogenesis 116 17932950
2000 DLC-1 is deleted in primary hepatocellular carcinoma and exerts inhibitory effects on the proliferation of hepatoma cell lines with deleted DLC-1. Cancer research 115 11118037
2006 The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation. Oncogene 112 16862168
2007 Deleted in liver cancer-1 (DLC-1): a tumor suppressor not just for liver. The international journal of biochemistry & cell biology 104 17521951
1999 Molecular cloning of a candidate tumor suppressor gene, DLC1, from chromosome 3p21.3. Cancer research 103 10213508
2003 Transcriptional silencing of the DLC-1 tumor suppressor gene by epigenetic mechanism in gastric cancer cells. Oncogene 100 12813468
2005 Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling. Oncogene 99 15674352
2011 Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK). Proceedings of the National Academy of Sciences of the United States of America 94 21969587
2003 Promoter hypermethylation of DLC-1, a candidate tumor suppressor gene, in several common human cancers. Cancer genetics and cytogenetics 94 12645648
2020 Colorectal cancer-derived exosomal miR-106b-3p promotes metastasis by down-regulating DLC-1 expression. Clinical science (London, England : 1979) 91 32065214
2009 Role of DLC-1, a tumor suppressor protein with RhoGAP activity, in regulation of the cytoskeleton and cell motility. Cancer metastasis reviews 91 19221866
2005 DLC-1, a Rho GTPase-activating protein with tumor suppressor function, is essential for embryonic development. FEBS letters 90 15710412
2002 The 14-kDa dynein light chain-family protein Dlc1 is required for regular oscillatory nuclear movement and efficient recombination during meiotic prophase in fission yeast. Molecular biology of the cell 77 11907273
2015 MicroRNA-106b promotes colorectal cancer cell migration and invasion by directly targeting DLC1. Journal of experimental & clinical cancer research : CR 73 26223867
2008 DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling. Journal of cell science 67 19066281
2014 DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis. The Journal of clinical investigation 66 24590291
2007 DLC-1, a GTPase-activating protein for Rho, is associated with cell proliferation, morphology, and migration in human hepatocellular carcinoma. Biochemical and biophysical research communications 65 17292327
2016 LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex. Structure (London, England : 1993) 63 27265849
2012 Differential regulation of the activity of deleted in liver cancer 1 (DLC1) by tensins controls cell migration and transformation. Proceedings of the National Academy of Sciences of the United States of America 63 22307599
2013 CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth. Proceedings of the National Academy of Sciences of the United States of America 58 24082123
2011 DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism. Cancer research 57 21372205
2018 Mechanotransduction in talin through the interaction of the R8 domain with DLC1. PLoS biology 56 30028837
2015 Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein-Barr virus-associated gastric carcinomas. Medical oncology (Northwood, London, England) 56 25720522
2008 Deleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma. PloS one 55 18648664
2008 Effects of structure of Rho GTPase-activating protein DLC-1 on cell morphology and migration. The Journal of biological chemistry 55 18786931
2018 Resveratrol promotes oxidative stress to drive DLC1 mediated cellular senescence in cancer cells. Experimental cell research 54 29964052
2009 p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. Oncogene 54 19151751
2010 Tensin 2 modulates cell contractility in 3D collagen gels through the RhoGAP DLC1. Journal of cellular biochemistry 52 20069572
2014 CDK5 is a major regulator of the tumor suppressor DLC1. The Journal of cell biology 51 25452387
2009 The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration. Journal of cell science 51 19158340
2009 Tensin1 requires protein phosphatase-1alpha in addition to RhoGAP DLC-1 to control cell polarization, migration, and invasion. The Journal of biological chemistry 51 19826001
2020 Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression. Journal of cellular and molecular medicine 48 32725802
2012 Role of DLC1 tumor suppressor gene and MYC oncogene in pathogenesis of human hepatocellular carcinoma: potential prospects for combined targeted therapeutics (review). International journal of oncology 48 22580498
2009 Deleted in liver cancer 1 (DLC1) utilizes a novel binding site for Tensin2 PTB domain interaction and is required for tumor-suppressive function. PloS one 48 19440389
2004 A PLCdelta1-binding protein, p122/RhoGAP, is localized in caveolin-enriched membrane domains and regulates caveolin internalization. Genes to cells : devoted to molecular & cellular mechanisms 47 14723705
2015 Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer. Proceedings of the National Academy of Sciences of the United States of America 46 26401016
2011 A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors. Oncogene 46 21217778
2003 Analysis of DLC-1 expression in human breast cancer. Journal of cancer research and clinical oncology 45 12759748
2012 Functional interaction of tumor suppressor DLC1 and caveolin-1 in cancer cells. Cancer research 43 22693251
2007 Morphological changes and nuclear translocation of DLC1 tumor suppressor protein precede apoptosis in human non-small cell lung carcinoma cells. Experimental cell research 42 17888903
2016 DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers. Oncotarget 41 27174913
2016 Curcumin inhibits growth of human breast cancer cells through demethylation of DLC1 promoter. Molecular and cellular biochemistry 39 27830358
2006 Aberrant methylation of the 8p22 tumor suppressor gene DLC1 in renal cell carcinoma. Cancer letters 39 17029774
2009 Simultaneous loss of the DLC1 and PTEN tumor suppressors enhances breast cancer cell migration. Experimental cell research 38 19482022
2008 DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway. Leukemia 37 18923442
2017 Receptor tyrosine kinase activation of RhoA is mediated by AKT phosphorylation of DLC1. The Journal of cell biology 36 29114068
2013 DLC1 induces expression of E-cadherin in prostate cancer cells through Rho pathway and suppresses invasion. Oncogene 36 23376848
2017 Hepatitis B core protein promotes liver cancer metastasis through miR-382-5p/DLC-1 axis. Biochimica et biophysica acta. Molecular cell research 35 28982593
2020 DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis. Journal of cell science 34 31964713
2015 MicroRNA-141 regulates the tumour suppressor DLC1 in colorectal cancer. Neoplasma 34 26278151
2019 DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA. The Journal of biological chemistry 32 31806702
2014 GAP-independent functions of DLC1 in metastasis. Cancer metastasis reviews 32 24338004
2014 Deleted in liver cancer-1 (DLC1): an emerging metastasis suppressor gene. Molecular diagnosis & therapy 32 24519699
2013 PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis. Nature communications 32 23511482
2009 DLC1 activation requires lipid interaction through a polybasic region preceding the RhoGAP domain. Molecular biology of the cell 32 19710422
2000 Sequence variants of DLC1 in colorectal and ovarian tumours. Human mutation 32 10649492
2016 miR-429 promotes the proliferation of non-small cell lung cancer cells via targeting DLC-1. Oncology letters 31 27602157
2012 DLC1 interaction with α-catenin stabilizes adherens junctions and enhances DLC1 antioncogenic activity. Molecular and cellular biology 31 22473989
2006 Genetic and epigenetic alterations of DLC-1, a candidate tumor suppressor gene, in nasopharyngeal carcinoma. Acta biochimica et biophysica Sinica 31 16680376
2015 DLC-1 induces mitochondrial apoptosis and epithelial mesenchymal transition arrest in nasopharyngeal carcinoma by targeting EGFR/Akt/NF-κB pathway. Medical oncology (Northwood, London, England) 30 25779535
2010 Identification and characterization of Dlc1 isoforms in the mouse and study of the biological function of a single gene trapped isoform. BMC biology 30 20199662
2017 Regulation of white and brown adipocyte differentiation by RhoGAP DLC1. PloS one 29 28358928
2016 IGF2-derived miR-483 mediated oncofunction by suppressing DLC-1 and associated with colorectal cancer. Oncotarget 29 27366946
2022 M2 Macrophage Derived Extracellular Vesicle-Mediated Transfer of MiR-186-5p Promotes Colon Cancer Progression by Targeting DLC1. International journal of biological sciences 28 35280693
2018 Stiffness-Induced Endothelial DLC-1 Expression Forces Leukocyte Spreading through Stabilization of the ICAM-1 Adhesome. Cell reports 28 30231995
2009 Overexpression of DLC-1 induces cell apoptosis and proliferation inhibition in the renal cell carcinoma. Cancer letters 28 19380190
2020 Combination of dihydroartemisinin and resveratrol effectively inhibits cancer cell migration via regulation of the DLC1/TCTP/Cdc42 pathway. Food & function 27 33150340
2019 A tumor suppressor DLC1: The functions and signal pathways. Journal of cellular physiology 27 31773748
2010 DLC1 negatively regulates angiogenesis in a paracrine fashion. Cancer research 26 20861185
2007 Tumor-specific methylation of the 8p22 tumor suppressor gene DLC1 is an epigenetic biomarker for Hodgkin, nasal NK/T-cell and other types of lymphomas. Epigenetics 25 17965626
2005 Epigenetic inactivation of DLC-1 in supratentorial primitive neuroectodermal tumor. Human pathology 25 15712180
2020 Isolation and Characterization of Bacillus cereus Phage vB_BceP-DLc1 Reveals the Largest Member of the Φ29-Like Phages. Microorganisms 24 33171789
2008 Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy. Cancer gene therapy 24 18369381
2022 Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions. Food & function 23 35234761
2018 The tumor suppressor DLC1 inhibits cancer progression and oncogenic autophagy in hepatocellular carcinoma. Laboratory investigation; a journal of technical methods and pathology 23 29785050
2014 Tumor suppressor DLC-1 induces apoptosis and inhibits the growth and invasion of colon cancer cells through the Wnt/β-catenin signaling pathway. Oncology reports 23 24604602
2011 Ursodeoxycholic acid-induced inhibition of DLC1 protein degradation leads to suppression of hepatocellular carcinoma cell growth. Oncology reports 23 21455586
2002 Gene structure, tissue expression, and linkage mapping of the mouse DLC-1 gene (Arhgap7). Gene 23 12034501
2016 Dynein light chain DLC-1 promotes localization and function of the PUF protein FBF-2 in germline progenitor cells. Development (Cambridge, England) 22 27864381
2008 Focal adhesion-localization of START-GAP1/DLC1 is essential for cell motility and morphology. Genes to cells : devoted to molecular & cellular mechanisms 22 19170769
2016 Dlc1 interaction with non-muscle myosin heavy chain II-A (Myh9) and Rac1 activation. Biology open 21 26977077
2015 H2O2 inhibits proliferation and mediates suppression of migration via DLC1/RhoA signaling in cancer cells. Asian Pacific journal of cancer prevention : APJCP 21 25743845
2011 Silencing of DLC1 upregulates PAI-1 expression and reduces migration in normal prostate cells. Molecular cancer research : MCR 21 22064653
2013 DLC-1, a candidate tumor suppressor gene, inhibits the proliferation, migration and tumorigenicity of human nasopharyngeal carcinoma cells. International journal of oncology 20 23588806
2012 Preclinical evaluation of combined antineoplastic effect of DLC1 tumor suppressor protein and suberoylanilide hydroxamic acid on prostate cancer cells. Biochemical and biophysical research communications 20 22425986
2022 SH3 domain regulation of RhoGAP activity: Crosstalk between p120RasGAP and DLC1 RhoGAP. Nature communications 19 35970859
2021 MIR-301b-3p Promotes Lung Adenocarcinoma Cell Proliferation, Migration and Invasion by Targeting DLC1. Technology in cancer research & treatment 19 33754907
2020 Cancer-Associated Point Mutations in the DLC1 Tumor Suppressor and Other Rho-GAPs Occur Frequently and Are Associated with Decreased Function. Cancer research 19 32606003
2019 MDT-28/PLIN-1 mediates lipid droplet-microtubule interaction via DLC-1 in Caenorhabditis elegans. Scientific reports 19 31624276
2017 Down-regulation of DLC1 in endothelial cells compromises the angiogenesis process. Cancer letters 19 28408355
2013 Inhibition of cell migration and invasion mediated by the TAT-RasGAP317-326 peptide requires the DLC1 tumor suppressor. Oncogene 19 24213569
2012 Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 19 22522847
2017 Asymmetric localization of DLC1 defines avian trunk neural crest polarity for directional delamination and migration. Nature communications 18 29084958
2003 Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study. Mutation research 17 12873722

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