Affinage

DLC1

Rho GTPase-activating protein 7 · UniProt Q96QB1

Round 2 corrected
Length
1528 aa
Mass
170.6 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLC1 is a focal adhesion-localized RhoGAP tumor suppressor that inactivates RhoA, RhoB, and RhoC to suppress Rho/ROCK/MLC2-mediated actomyosin contractility, cell migration, and tumorigenesis across multiple tissue types (PMID:14633684, PMID:17932950, PMID:18648664, PMID:18519636). Its GAP activity is held in check by intramolecular autoinhibition — the N-terminal region binds the RhoGAP domain in a closed monomeric conformation — which is relieved by CDK5 phosphorylation and PKA-induced dimerization, while AKT phosphorylation re-imposes autoinhibition and p120RasGAP SH3 domain binding directly occludes the catalytic arginine finger (PMID:25452387, PMID:23511482, PMID:29114068, PMID:35970859). Full tumor suppressor function requires focal adhesion recruitment through an LD-like motif that binds talin and FAK, tensin/cten SH2-domain interactions, PI(4,5)P2-mediated stimulation of GAP activity, and a RhoGAP-independent START domain–caveolin-1 interaction (PMID:21969587, PMID:17190795, PMID:19710422, PMID:22693251). In melanoma, nuclear DLC1 paradoxically functions as an oncogene by cooperating with FOXK1 to transcriptionally activate MMP9 and promote invasion independently of RhoGAP activity (PMID:32214200).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1998 High

    Identification of DLC1 as a candidate tumor suppressor at 8p21.3-22, deleted in hepatocellular carcinoma, resolved the question of which gene at this frequently lost locus encodes a RhoGAP-homologous protein.

    Evidence Representational difference analysis cloning from primary HCC with LOH and expression analysis across HCC lines

    PMID:9605766

    Open questions at the time
    • No enzymatic GAP activity demonstrated at this stage
    • Tumor suppressor activity not functionally validated
  2. 2003 High

    Demonstrating that DLC1 possesses direct GAP activity toward RhoA and Cdc42, and that its re-expression suppresses tumorigenicity, established it as a bona fide RhoGAP tumor suppressor inactivated by both LOH and promoter methylation.

    Evidence In vitro GAP assay for substrate specificity; colony formation and nude mouse xenograft upon DLC1 restoration in breast and HCC lines; methylation-specific PCR

    PMID:12545165 PMID:14633684 PMID:14647417

    Open questions at the time
    • Mechanism of autoinhibition not yet identified
    • Subcellular targeting mechanism unknown
  3. 2005 High

    Genetic ablation of DLC1 in mice revealed its essential role in embryonic development and actin/focal adhesion organization, establishing that DLC1 GAP activity is required for organismal viability.

    Evidence Homologous recombination knockout mouse; embryonic lethality by E10.5 with neural tube, heart, and placental defects; cytoskeletal phenotype in primary fibroblasts

    PMID:15710412

    Open questions at the time
    • Specific Rho substrates responsible for embryonic lethality not determined
    • Tissue-specific requirements not dissected
  4. 2006 High

    Discovery that tensin family SH2 domains recruit DLC1 to focal adhesions — and that this localization is essential for tumor suppression — answered how DLC1 reaches its site of action and separated localization from catalytic requirements.

    Evidence Co-IP with mutagenesis of cten SH2-binding residues; focal adhesion targeting fusion rescue of mislocalized DLC1 mutants

    PMID:16951145 PMID:17190795

    Open questions at the time
    • Additional focal adhesion targeting mechanisms not yet identified
    • Caveolae vs. focal adhesion functional contributions not separated
  5. 2007 High

    Separation-of-function mutagenesis demonstrated that tensin1 binding (via Y442) and RhoGAP activity are independently necessary for full DLC1 tumor suppression, establishing a two-component requirement model.

    Evidence Y442F mutant retains GAP activity but loses focal adhesion localization and tumor suppressor function; tested with Rho-GTP and biological assays in PNAS

    PMID:17517630 PMID:17932950

    Open questions at the time
    • How focal adhesion localization enhances tumor suppression beyond Rho inactivation not resolved
  6. 2008 High

    Identification of the Rho/ROCK/MLC2 pathway as the primary downstream effector, validated by in vivo genetic epistasis showing RhoA knockdown selectively kills DLC1-deficient hepatoma cells, defined the signaling axis through which DLC1 exerts tumor suppression.

    Evidence Phospho-MLC2/MYPT1 readouts with GAP-dead mutant and dominant-active ROCK rescue; mosaic mouse HCC model with constitutive RhoA and RhoA siRNA epistasis

    PMID:18519636 PMID:18648664

    Open questions at the time
    • Whether effectors beyond ROCK contribute to DLC1-mediated tumor suppression in specific tissues
  7. 2008 High

    14-3-3 binding at phosphoserines 327 and 431, induced by PKC/PKD signaling, was shown to inhibit DLC1 GAP activity and block nucleocytoplasmic shuttling, establishing the first post-translational negative regulatory mechanism.

    Evidence In vitro GAP assay demonstrating 14-3-3-mediated inhibition; phospho-site mutagenesis; nuclear/cytoplasmic fractionation after phorbol ester treatment

    PMID:19066281

    Open questions at the time
    • Physiological signals triggering PKD-mediated DLC1 phosphorylation in vivo not defined
    • Nuclear function of DLC1 not yet explored
  8. 2009 High

    Discovery that PI(4,5)P2 binding through a polybasic region stimulates DLC1 GAP activity, and that the SAM domain binds EF1A1 to promote migration GAP-independently, revealed two additional activation/functional modules beyond the RhoGAP domain.

    Evidence In vitro lipid-stimulated GAP assay with PBR mutagenesis; NMR structure of SAM domain; SAM mutagenesis abolishing EF1A1 binding and migration

    PMID:19158340 PMID:19710422

    Open questions at the time
    • How PI(4,5)P2 binding integrates with autoinhibition not known
    • SAM-EF1A1 downstream effectors unclear
  9. 2011 High

    Identification of the LD-like motif that binds talin and FAK provided a second focal adhesion targeting mechanism independent of tensin SH2 binding, explaining how DLC1 integrates into the focal adhesion protein network.

    Evidence Co-IP and mutagenesis of LD motif (469-476); LD mutants diffusely cytoplasmic but GAP-active yet tumor-suppression impaired

    PMID:21969587

    Open questions at the time
    • Relative contributions of LD-talin vs. tensin-SH2 targeting not quantified in vivo
  10. 2012 High

    Mapping the START domain–caveolin-1 interaction and the DLC1–α-catenin adherens junction complex identified two RhoGAP-independent tumor suppressive mechanisms, broadening DLC1 function beyond catalytic Rho inactivation.

    Evidence START domain mutagenesis disrupting CAV-1 binding with retained GAP activity but lost growth suppression; α-catenin domain mapping with Co-IP and E-cadherin/β-catenin adherens junction colocalization

    PMID:22473989 PMID:22693251

    Open questions at the time
    • Molecular basis of START domain–CAV-1 interaction not structurally resolved
    • Whether α-catenin binding and START-CAV-1 interactions are independent or cooperative
  11. 2014 High

    CDK5 phosphorylation of four N-terminal serines was shown to relieve autoinhibition (N-terminal domain binding to RhoGAP domain), coordinately activating GAP activity, tensin/talin binding, and focal adhesion localization — providing the first complete mechanistic model of DLC1 activation.

    Evidence In vitro kinase assay, MS phospho-site identification, reconstituted intramolecular autoinhibitory binding, Co-IP and immunofluorescence

    PMID:25452387

    Open questions at the time
    • Signals regulating CDK5 activity toward DLC1 in vivo not identified
  12. 2016 High

    The crystal structure of talin R8 bound to the DLC1 LD motif revealed the atomic basis of focal adhesion recruitment and competition with paxillin, while DLC1 was shown to be required for adipocyte differentiation via Rho-ROCK suppression.

    Evidence X-ray co-crystal structure with mutagenesis; Dlc1-KO MEF adipogenesis failure rescued by ROCK inhibitors; ChIP showing PPARγ binds Dlc1 promoter

    PMID:27265849 PMID:28358928

    Open questions at the time
    • Whether paxillin-DLC1 competition at talin R8 is regulated dynamically in cells
    • DLC1 role in adipose tissue in vivo not tested
  13. 2017 High

    AKT phosphorylation was identified as the mechanism that re-imposes autoinhibition downstream of RTK signaling, converting active DLC1 dimers to inactive monomers and establishing a closed regulatory cycle (CDK5 opens, AKT closes).

    Evidence In vitro AKT kinase assay, MS-identified phospho-sites S298/S329/S567, intramolecular binding reconstitution, dimer-to-monomer transition, AKT inhibitor rescue in cancer model

    PMID:29114068

    Open questions at the time
    • How CDK5 and AKT activities are spatially coordinated at focal adhesions
  14. 2018 High

    Biophysical studies showed that mechanical force-induced unfolding of talin R8 releases DLC1 to increase local RhoA activity, placing DLC1 as a mechanotransduction effector linking integrin force sensing to Rho signaling.

    Evidence Engineered unfolding-resistant talin R8 mutant, AFM, traction force microscopy, RhoA activity measurement

    PMID:30028837

    Open questions at the time
    • Whether force-dependent DLC1 release occurs at specific adhesion maturation stages in vivo
  15. 2019 High

    TNS3 and PTEN C2 domain peptides were shown to relieve SAM–RhoGAP autoinhibition, identifying a peptide-accessible regulatory interface and demonstrating that DLC1 possesses at least two distinct autoinhibitory interactions (N-terminal/RhoGAP and SAM/RhoGAP).

    Evidence In vitro SAM-C2 domain binding, peptide competition assays, cell-permeable TAT-peptide and cyclic peptide functional assays

    PMID:31806702

    Open questions at the time
    • Relative contribution of SAM-mediated vs. N-terminal autoinhibition not quantified
    • Structural basis of SAM-RhoGAP interaction unknown
  16. 2020 High

    Systematic analysis of cancer-associated DLC1 mutations confirmed that inactivation occurs through multiple distinct mechanisms — loss of GAP activity, loss of 14-3-3 regulation, and loss of START-CAV-1 binding — while nuclear DLC1 in melanoma was shown to act as an oncogene by co-activating MMP9 transcription with FOXK1.

    Evidence In vitro GAP assay of cancer mutants with binding and cellular assays; MS-identified FOXK1 interaction, ChIP at MMP9 promoter, invasion/metastasis assays

    PMID:32214200 PMID:32606003

    Open questions at the time
    • Context-dependent switch from tumor suppressor to oncogene not mechanistically explained
    • Whether FOXK1-DLC1 nuclear interaction occurs in non-melanoma cancers
  17. 2021 High

    Cytoplasmic EZH2 methylation targeting DLC1 for CUL-4A-dependent proteasomal degradation identified a KRAS-driven post-translational mechanism of DLC1 protein destabilization, and combined EZH2/AKT/SRC inhibition potently reactivated DLC1 tumor suppression.

    Evidence siRNA knockdown of EZH2/CUL-4A/KRAS, IP for methylation and ubiquitination, pharmacological inhibitor combinations, DLC1-dependent tumor growth assays

    PMID:34862367

    Open questions at the time
    • Specific methylation site(s) on DLC1 not mapped
    • Whether EZH2-mediated DLC1 degradation operates in non-KRAS-driven cancers
  18. 2022 High

    The co-crystal structure of p120RasGAP SH3 domain bound to the DLC1 RhoGAP domain revealed direct occlusion of the RhoA binding surface and catalytic arginine finger, providing atomic-resolution understanding of trans-inhibition of DLC1.

    Evidence X-ray co-crystallography of SH3-RhoGAP complex, mutagenesis of interface residues, in vitro GAP activity measurement

    PMID:35970859

    Open questions at the time
    • Physiological conditions under which p120RasGAP inhibits DLC1 in cells not defined
    • Whether Ras-GTP loading of p120RasGAP modulates DLC1 inhibition

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how the multiple autoinhibitory mechanisms (N-terminal/RhoGAP, SAM/RhoGAP, 14-3-3, p120RasGAP SH3) are integrated and hierarchically organized in vivo, the structural basis of full-length DLC1 in open vs. closed conformations, the mechanistic basis for the context-dependent switch to oncogenic function in melanoma, and whether therapeutic reactivation of DLC1 via combined kinase/EZH2 inhibition is effective in vivo.
  • No full-length DLC1 structure available
  • In vivo hierarchy of regulatory inputs not resolved
  • Therapeutic strategies targeting DLC1 reactivation not clinically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 5 GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0008289 lipid binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 6 GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1500931 Cell-Cell communication 1
Partners
CAV1CTNNA1FOXK1RASA1RHOATLN1TNS1TNS4
Complex memberships
DLC1–caveolin-1 (START domain-mediated)DLC1–talin (R8 domain)DLC1–tensin/cten (SH2-mediated)DLC1–α-catenin–E-cadherin adherens junction complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 DLC1 was cloned from primary hepatocellular carcinoma, encodes a 1091-amino acid protein with 86% homology to rat p122 RhoGAP, and was localized to chromosome 8p21.3-22. Loss of heterozygosity was detected in 7/16 primary HCCs and 10/11 HCC cell lines, and DLC1 mRNA was absent in 4/14 HCC cell lines, establishing it as a candidate tumor suppressor with RhoGAP homology. Representational difference analysis, LOH analysis, Northern blot, FISH chromosomal mapping Cancer research High 9605766
2003 DLC1 protein was established as a GTPase-activating protein with specific activity for RhoA and Cdc42 in an in vitro GAP activity assay. CpG island methylation in the DLC1 promoter was found in 3/7 HCC cell lines and 6/25 primary HCCs, demonstrating epigenetic silencing as a mechanism of inactivation alongside LOH. In vitro GTPase-activating protein activity assay, LOH analysis (100 HCC cases), methylation-specific PCR, real-time quantitative PCR Cancer research High 14633684
2003 Restoration of DLC1 expression in breast carcinoma cell lines lacking endogenous DLC1 caused significant growth inhibition, reduction of colony formation, and abolished in vivo tumorigenicity in nude mice, establishing DLC1 as a bona fide tumor suppressor gene in breast cancer. cDNA transfection, colony formation assay, xenograft tumor formation in nude mice Oncogene High 12545165
2004 Restoration of DLC1 expression in hepatocellular carcinoma cell lines induced caspase-3-mediated apoptosis, inhibited cell growth and invasiveness in vitro, and reduced tumor formation in nude mice. DLC1 protein was localized to the cell cytoplasm by immunostaining. cDNA transfection, caspase-3 activity assay, immunostaining for subcellular localization, invasion assay, xenograft model Oncogene High 14647417
2004 DLC1 suppresses non-small cell lung carcinoma (NSCLC) growth and tumorigenicity. DLC1 exhibited strong GAP activity for RhoA, RhoB, and RhoC but only very limited activity for Cdc42 in vitro when assayed as full-length protein, whereas the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for all four GTPases, implying autoinhibition of the full-length protein. DLC1 dramatically reduces RhoA activity at the leading edge of cellular protrusions as shown by a RhoA biosensor. In vitro RhoGAP activity assay (full-length vs. isolated domain), RhoA FRET biosensor, anchorage-dependent and -independent growth assays, invasion assay, nude mouse xenograft Molecular carcinogenesis High 17932950
2005 Homozygous inactivation of mouse DLC1 (Arhgap7) by homologous recombination is embryonic lethal by day 10.5 post coitum, with defects in neural tube, brain, heart, and placenta. DLC1-deficient fibroblasts displayed alterations in actin filament organization and focal adhesion structure, demonstrating an essential developmental role for DLC1 GAP activity in vivo. Homologous recombination knockout mouse, histological analysis, immunofluorescence of actin/focal adhesions in primary fibroblasts FEBS letters High 15710412
2006 DLC1 interacts with the SH2 domain of cten (C-terminal tensin-like) in a phosphotyrosine-independent manner. Site-directed mutagenesis identified residues on both cten and DLC1 essential for interaction. Disruption of this interaction abrogated DLC1 focal adhesion localization and eliminated tumor suppression activity; fusing these DLC1 mutants to a focal adhesion targeting sequence significantly restored tumor suppressor activity, demonstrating that focal adhesion localization mediated by cten is essential for DLC1 function. Co-immunoprecipitation, site-directed mutagenesis, immunofluorescence, focal adhesion targeting fusion constructs, colony formation assay The Journal of cell biology High 17190795
2006 DLC1 interacts with tensin2 directly in vitro and in vivo. Both proteins co-localize to punctate cytoplasmic structures and interact with endogenous caveolin-1 (a major structural component of caveolae) via caveolin-1 binding motifs present in both DLC1 and tensin2, suggesting that the DLC1-tensin2 complex acts within caveolae to regulate Rho GTPases and cytoskeletal reorganization. In vitro binding assay, co-immunoprecipitation, immunofluorescence co-localization, sequence analysis of caveolin-binding motifs Cancer research Medium 16951145
2007 DLC1 tumor suppressor activity requires cooperation between its tensin-binding activity and its RhoGAP activity. DLC1 binds tensin1 through both the tensin SH2 and PTB domains. The SH2 binding depends on a specific tyrosine (Y442) in DLC1 but is phosphotyrosine-independent—an unusual feature for SH2 binding. The Y442F mutant is diffusely cytoplasmic (not focal adhesion-localized) but retains RhoGAP activity, yet shows markedly reduced biological tumor suppressor activity, demonstrating that focal adhesion localization via tensin binding is required for full function independently of RhoGAP activity. Co-immunoprecipitation, point mutagenesis (Y442F and RhoGAP-dead mutants), immunofluorescence, Rho-GTP measurement, biological activity assays Proceedings of the National Academy of Sciences of the United States of America High 17517630
2008 DLC1 negatively regulates the Rho/ROCK/MLC2 signaling pathway in hepatocellular carcinoma. Ectopic DLC1 expression abolished Rho/ROCK-mediated stress fiber and focal adhesion formation, downregulated cortical phosphorylation of myosin light chain 2 (MLC2), and inhibited ROCK-related MYPT1 phosphorylation at Thr853. These effects were dependent on RhoGAP activity, as the DLC1 K714E RhoGAP-deficient mutant abolished them. Expression of dominant-active ROCK rescued cells from DLC1-induced cytoskeletal collapse. Ectopic expression, immunofluorescence, Western blot (MLC2 and MYPT1 phosphorylation), RhoGAP-deficient mutant (K714E), dominant-active ROCK rescue experiment PloS one High 18648664
2008 DLC1 activity is regulated by phorbol-ester-induced activation of protein kinase C and protein kinase D, which stimulates association of DLC1 with 14-3-3 adaptor proteins via phosphoserine recognition motifs involving Ser327 and Ser431. Association with 14-3-3 proteins inhibits DLC1 GAP activity and blocks DLC1 nucleocytoplasmic shuttling, likely by masking a nuclear localization sequence. Co-immunoprecipitation, in vitro GAP activity assay, site-directed mutagenesis (Ser327, Ser431), nuclear/cytoplasmic fractionation, phorbol ester treatment Journal of cell science High 19066281
2008 DLC1 localizes to focal adhesions via a 'focal adhesion-targeting (FAT) domain' (amino acids 265–459). This localization is required for DLC1-mediated morphological change (cell rounding) and regulation of cell migration and spreading. Expression of the FAT domain alone acts as a dominant negative, dissociating endogenous DLC1 from focal adhesions and reducing cell migration and spreading. DLC1 regulates actin rearrangement through down-regulation of active RhoA and Cdc42. Immunofluorescence, domain deletion mapping, dominant-negative FAT domain expression, cell migration and spreading assays Genes to cells Medium 19170769
2008 p122/DLC1 localizes to caveolin-enriched membrane domains (caveolae) via its GAP domain, in a manner dependent on membrane cholesterol levels. Transient expression of DLC1 causes internalization of caveolin-1 and reorganizes F-actin, suggesting that DLC1 plays a role in caveolin distribution through actin cytoskeleton reorganization. EGFP-tagged protein expression, immunofluorescence, sucrose density gradient centrifugation, cholesterol depletion experiments Genes to cells Medium 14723705
2009 The SAM domain of DLC1 (but not DLC2) binds eukaryotic elongation factor 1A1 (EF1A1), identified by protein precipitation and mass spectrometry. NMR solution structure of DLC1 SAM revealed a monomeric four-helix fold. Mutation of hydrophobic patch residues F38, L39, and F40 abolished EF1A1 interaction. DLC1 SAM facilitates EF1A1 distribution to membrane periphery/ruffles upon growth factor stimulation. The DLC1 SAM domain promotes cell migration in a GAP-independent, EF1A1-interaction-dependent manner. Protein precipitation, mass spectrometry, NMR structure determination, site-directed mutagenesis, immunofluorescence, cell migration assay Journal of cell science High 19158340
2009 DLC1 binds phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) through a polybasic region (PBR) adjacent to its RhoGAP domain. PI(4,5)P2-containing membranes stimulate DLC1 GAP activity in vitro. In cells, a DLC1 PBR mutant inactivates Rho signaling less efficiently and is severely impaired in suppressing cell spreading, directed migration, and proliferation, establishing PI(4,5)P2 as a cofactor for DLC1 activation. Lipid-binding assay, in vitro GAP activity assay with PI(4,5)P2-containing membranes, site-directed mutagenesis of PBR, cell spreading/migration/proliferation assays Molecular biology of the cell High 19710422
2009 DLC1 interacts with tensin2 through a novel phosphotyrosine-binding (PTB) domain-dependent binding site at DLC1 residues 375–385, distinct from previously identified tensin SH2 domain interactions. Removal of this PTB-binding site partially reduced RhoGAP activity and attenuated DLC1 growth-suppressive activity, while not affecting focal adhesion localization or interactions with tensin1 and cten. Co-immunoprecipitation, deletion mutagenesis, immunofluorescence, RhoGAP activity assay, growth suppression assay PloS one Medium 19440389
2010 Tensin 2 negatively regulates DLC1 to permit Rho-mediated actomyosin contraction. Tensin 2 knockdown significantly reduced the ability of human foreskin fibroblasts to contract 3D collagen gels and was associated with reduced Rho activity. This effect was reversed by co-depletion of DLC1, establishing a tensin 2 → DLC1 (inhibition) → RhoA → actomyosin contraction pathway in fibroblasts. siRNA knockdown of tensin isoforms and DLC1, 3D collagen gel contraction assay, Rho activity measurement, live-cell imaging Journal of cellular biochemistry High 20069572
2010 Protein kinase D (PKD) phosphorylates DLC1 at Ser807 within the GAP domain, as identified by mass spectrometry and validated with a phospho-Ser807-specific antibody. While Ser807 phosphorylation did not directly alter in vitro GAP activity, a Ser807Ala DLC1 mutant inhibited colony formation more potently than wild-type, indicating that PKD-mediated phosphorylation negatively regulates DLC1 cellular function. Mass spectrometry phospho-site mapping, phospho-specific antibody, in vitro GAP activity assay, colony formation assay with S807A mutant Experimental cell research Medium 21087603
2011 DLC1 contains an LD-like motif (residues 469LDDILYHV476) that binds both talin and focal adhesion kinase (FAK). This motif is necessary for DLC1 localization to focal adhesions; LD-like motif mutants are diffusely cytoplasmic but retain RhoGAP activity yet display reduced tumor suppressor activity, indicating that talin and FAK binding via this motif is required for full DLC1 tumor suppressor function independently of Rho-GTP regulation. Co-immunoprecipitation, site-directed mutagenesis (deletion and substitution mutants), immunofluorescence, Rho-GTP measurement, biological activity assays (anchorage-independent growth, tumor formation) Proceedings of the National Academy of Sciences of the United States of America High 21969587
2012 DLC1 interacts with α-catenin; their binding is mediated by DLC1 N-terminal residues 340–435 and α-catenin N-terminal residues 117–161. The DLC1–α-catenin complex reduces RhoA-GTP at the plasma membrane, associates with E-cadherin and β-catenin at adherens junctions, requires DLC1 GAP activity for membrane accumulation, and stabilizes adherens junctions. This mechanism contributes to DLC1 oncosuppressive activity in prostate carcinoma cells. Co-immunoprecipitation, domain mapping mutagenesis, immunofluorescence co-localization, Rho-GTP measurement at membrane, siRNA knockdown, oncosuppression assays Molecular and cellular biology High 22473989
2012 DLC1 forms a complex with caveolin-1 (CAV-1), and the interaction is mapped to the DLC1 START domain. START domain mutations disrupted DLC1-CAV-1 interaction and colocalization. DLC1 with a START domain mutation failed to suppress neoplastic growth despite retaining RhoGAP activity, demonstrating that DLC1 START domain-CAV-1 interaction contributes to tumor suppression via a RhoGAP-independent mechanism. Co-immunoprecipitation, domain mapping mutagenesis, immunofluorescence, anchorage-independent growth assay, Rho-GTP measurement Cancer research High 22693251
2013 Cyclic AMP-dependent protein kinase A (PKA) phosphorylates DLC1 at Ser549, which enhances RhoGAP activity and promotes DLC1 dimerization. Ser549 phosphorylation-induced dimerization is required for enhanced tumor suppressor activity: inducible dimerization of a Ser549-deletion DLC1 rescues tumor suppressive and RhoGAP activities. This establishes PKA-induced dimerization as a novel mechanism regulating DLC1 RhoGAP activity. In vitro kinase assay, phospho-site mutagenesis, in vitro RhoGAP activity assay, co-immunoprecipitation for dimerization, in vitro and in vivo tumor suppression assays Nature communications High 23511482
2014 CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the RhoGAP domain. When unphosphorylated, this N-terminal region acts as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by binding to the RhoGAP domain. CDK5 phosphorylation relieves this autoinhibition, coordinately activating DLC1 localization to focal adhesions, RhoGAP activity, and binding to tensin and talin. Inhibition of CDK5 thus inactivates DLC1's tumor suppressor function. In vitro kinase assay, mass spectrometry phospho-site identification (4 serines), intramolecular binding assay (autoinhibition domain binds RhoGAP domain), co-immunoprecipitation (tensin/talin binding), immunofluorescence, RhoGAP activity assay The Journal of cell biology High 25452387
2016 The crystal structure of the talin R8 domain bound to the DLC1 LD motif was solved, revealing that the DLC1 LD motif forms a helix that binds the four-helix bundle of talin R8 in a canonical triple-helix arrangement. The same R8 surface also binds paxillin LD1 and LD2 motifs, indicating competitive interactions. Key charged residues stabilizing R8-LD interactions were identified and their importance validated in vitro and in cells. X-ray crystallography (co-crystal structure), in vitro binding assays, site-directed mutagenesis, cell-based functional assays Structure High 27265849
2017 Multiple receptor tyrosine kinase (RTK) ligands increase RhoA-GTP levels in a manner dependent on AKT activation. AKT phosphorylates three serines (S298, S329, S567) in the DLC1 N-terminal region, inducing strong intramolecular binding of this N-terminal region to the RhoGAP domain, converting DLC1 from an open, active dimer to a closed, inactive monomer, thereby reducing RhoA-GTP hydrolysis, DLC1 ligand binding, and focal adhesion colocalization. In vitro AKT kinase assay, mass spectrometry phospho-site identification, intramolecular binding assay, Rho-GTP measurement, co-immunoprecipitation, immunofluorescence, transgenic cancer model, AKT inhibitor treatment The Journal of cell biology High 29114068
2017 DLC1 is asymmetrically localized to the cytoplasm at the cell front in avian trunk neural crest cells (NCCs), where it suppresses RhoA activity, while RhoA is highly active at the cell rear. This asymmetric DLC1 localization requires its association with NEDD9. Loss of DLC1 or its asymmetric localization disrupts NCC polarity, directional delamination, and migration. SOX10 regulates DLC1 expression, and SOX9 regulates NEDD9, establishing a SOX9/SOX10–NEDD9/DLC1–RhoA regulatory axis for NCC migratory polarization. RHOA biosensor (in vivo and in vitro), siRNA/morpholino knockdown, immunofluorescence, co-immunoprecipitation (DLC1-NEDD9), in vivo neural crest delamination/migration assays in chick embryo Nature communications High 29084958
2017 DLC1 regulates endothelial cell migration and tube formation through distinct mechanisms. Silencing DLC1 enhances cell migration (through increased RhoA activity) but reduces tube formation. Further silencing of RhoA restores migration but not tube formation, while paxillin knockdown rescues both tube formation and migration. This establishes that DLC1 regulates endothelial migration through RhoA and tube formation mainly via paxillin, through independent pathways. siRNA knockdown, RhoA activity assay, cell migration assay, tube formation assay, endothelial-specific conditional knockout mice (DLC1-Tek), gel plug and aortic ring angiogenesis assays Cancer letters High 28408355
2018 Talin R8 domain unfolding under mechanical force controls DLC1 downstream signaling. Using a talin mutant resistant to force-induced unfolding of R8, DLC1 binding to folded talin suppresses RhoA-dependent cell contractility. When talin R8 is force-unfolded, DLC1 is released and RhoA activity increases, altering cell mechanics. This identifies mechanical unfolding of the talin R8 domain as a mechanotransduction mechanism that controls DLC1-RhoA signaling. Protein engineering (talin R8 unfolding-resistant mutant), atomic force microscopy, biophysical force measurements, RhoA activity assay, traction force microscopy PLoS biology High 30028837
2019 The DLC1 SAM domain binds specific peptide motifs within the C2 domains of tensin-3 (TNS3) and PTEN, and this interaction relieves DLC1 autoinhibition (the intramolecular SAM–RhoGAP interaction). Cell-permeable C2-derived peptides (TAT-fused) that compete for SAM domain binding promoted DLC1 RhoGAP activity, reduced RhoA activation, and inhibited tumor cell growth and migration. A cyclic version of the TNS3-C2 peptide effectively entered cancer cells and inhibited migration. In vitro domain-domain interaction assay, peptide competition assay, cell-permeable TAT-peptide delivery, RhoA-GTP measurement, soft-agar growth assay, cell migration assay The Journal of biological chemistry High 31806702
2020 DLC1 is a direct transcriptional target of the YAP/TAZ-TEAD complex in endothelial cells. Substrate stiffening and VEGF stimuli promote DLC1 expression in a YAP/TAZ-dependent manner. DLC1 limits F-actin fiber formation, integrin-based focal adhesion lifetime, and integrin-mediated traction forces. Depletion of endothelial DLC1 perturbs cell polarization in collective migration and inhibits angiogenic sprouting; ectopic DLC1 expression restores migration and sprouting in YAP-depleted cells. Chromatin immunoprecipitation (YAP/TAZ-TEAD binding to DLC1 promoter), siRNA knockdown, constitutively active YAP expression, live-cell imaging, traction force microscopy, in vitro sprouting assay Journal of cell science High 31964713
2020 Cancer-associated point mutations in the DLC1 RhoGAP domain are deficient for RhoGAP activity and for suppressing cell migration and anchorage-independent growth (7 of 9 tested RhoGAP domain mutants). A DLC1 linker region mutant showed reduced 14-3-3 binding, while a START domain mutant showed reduced caveolin-1 binding, both with impaired tumor suppressor function despite normal RhoGAP activity, demonstrating that multiple molecular mechanisms underlie cancer-associated DLC1 inactivation. In vitro RhoGAP activity assay, co-immunoprecipitation (14-3-3, caveolin-1 binding), cell migration assay, anchorage-independent growth assay, TCGA mutational analysis Cancer research High 32606003
2020 In melanoma cells (where DLC1 is highly expressed), nuclear-localized DLC1 functions as an oncogene rather than tumor suppressor. Mass spectrometry identified FOXK1 transcription factor as a DLC1-associated nuclear protein. FOXK1 mediates translocation and retention of DLC1 in the nucleus in a RhoGAP-independent manner. DLC1 and FOXK1 cooperatively activate MMP9 transcription through FOXK1-regulated promoter occupancy, promoting melanoma invasion and metastasis. Mass spectrometry (nuclear DLC1 interactome), co-immunoprecipitation (DLC1-FOXK1), immunofluorescence (nuclear localization), RNA-seq, ChIP (FOXK1 promoter occupancy at MMP9), invasion/metastasis assays Oncogene High 32214200
2021 DLC1 protein is post-translationally destabilized by cytoplasmic EZH2 methyltransferase, leading to CUL-4A ubiquitin-dependent proteasomal degradation. KRAS knockdown reduces cytoplasmic EZH2 levels and increases DLC1 protein. Pharmacologic inhibition of EZH2, CUL-4A, or the proteasome increases DLC1 steady-state protein levels. Additional kinase inhibition of AKT and/or SRC (which directly phosphorylate DLC1) further enhances DLC1 tumor suppressor activity, producing potent tumor growth inhibition with markers of apoptosis and senescence in a DLC1-dependent manner. siRNA knockdown (EZH2, CUL-4A, KRAS), pharmacological inhibitor treatment, immunoprecipitation for methylation and ubiquitination, proteasome inhibition, DLC1-dependent tumor growth assays Nature communications High 34862367
2022 The p120RasGAP SH3 domain directly binds the DLC1 RhoGAP domain at a site partially overlapping the RhoA binding site and impinging on the catalytic arginine finger. The co-crystal structure of the p120RasGAP SH3 domain bound to DLC1 RhoGAP was solved. Mutagenesis of the interface relieves SH3-mediated inhibition of DLC1 RhoGAP activity, revealing the structural mechanism by which p120RasGAP inhibits DLC1 GAP function. X-ray co-crystallography (SH3-RhoGAP complex), in vitro RhoGAP activity assay, site-directed mutagenesis of interface residues Nature communications High 35970859
2008 DLC1 knockdown cooperates with Myc to promote hepatocellular carcinoma in a mosaic mouse model. Cells with reduced DLC1 contain increased GTP-bound RhoA. Expression of constitutively activated RhoA mimics DLC1 loss in promoting hepatocarcinogenesis. Conversely, RhoA downregulation selectively inhibits tumor growth of hepatoma cells with disabled DLC1, establishing genetic epistasis between DLC1 and RhoA in HCC development. In vivo mosaic mouse HCC model (shRNA knockdown + Myc), constitutively active RhoA expression, RhoA-specific siRNA knockdown, Rho-GTP pulldown assay, tumor growth assay Genes & development High 18519636
2016 Dlc1 knockout mouse embryonic fibroblasts completely fail to differentiate into adipocytes, but this phenotype can be rescued by inhibitors of Rho-associated kinase (ROCK) and filamentous actin (F-actin), establishing that DLC1 promotes white and brown adipocyte differentiation through suppression of the Rho-ROCK pathway. PPARγ binds to the Dlc1 gene promoter and regulates its expression during adipogenesis. Dlc1-/- mouse embryonic fibroblasts, adipocyte differentiation assays, ROCK inhibitor rescue, ChIP (PPARγ binding to Dlc1 promoter), siRNA knockdown, mitochondrial respiration measurement PloS one High 28358928
2016 DLC1 interacts with non-muscle myosin heavy chain II-A (Myh9) in multiprotein complexes identified by mass spectrometry in Dlc1-overexpressing cells, and also interacts with plectin and spectrin proteins. Dlc1 overexpression leads to increased Myh9 phosphorylation and activation of Rac1 GTPase, providing a molecular basis for Dlc1-induced cell elongation morphology. Affinity purification-mass spectrometry (three major Dlc1 isoforms), co-immunoprecipitation validation, phospho-Myh9 Western blot, Rac1 activation assay Biology open Medium 26977077
2011 UDCA inhibits proteasomal degradation of DLC1 protein in a ubiquitin-independent manner, extending DLC1 protein half-life and reducing RhoA activity in hepatocellular carcinoma cells. Growth suppression by UDCA was reversed by DLC1 siRNA, and Rho inhibitor treatment restored reduced proliferation caused by DLC1 knockdown, placing DLC1-RhoA in the UDCA anti-proliferative pathway. Protein half-life assay (cycloheximide chase), ubiquitination immunoprecipitation, siRNA knockdown, Rho activity assay, MTS proliferation assay Oncology reports Medium 21455586
2008 TSA (trichostatin A), a histone deacetylase inhibitor, activates DLC1 promoter activity through two specific Sp1 sites at −219 and −174 relative to the transcription start site. Sp1 (but not Sp3) specifically binds these sites and enhances TSA-responsiveness. p300 coactivator is required for TSA-mediated DLC1 transcriptional activation, as p300 overexpression increased and p300 knockdown reduced TSA-induced DLC1 promoter activity. Promoter reporter assay, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis of Sp1 sites, p300 overexpression and siRNA knockdown Experimental & molecular medicine Medium 19116449

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2012 Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PloS one 312 23251661
1998 Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer research 297 9605766
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2012 Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. Molecular psychiatry 194 22688191
2003 Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer research 166 14633684
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
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
2009 Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling. Gut 157 19240061
2021 Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR. Theranostics 146 33391541
2007 Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities. Proceedings of the National Academy of Sciences of the United States of America 141 17517630
2006 The phosphotyrosine-independent interaction of DLC-1 and the SH2 domain of cten regulates focal adhesion localization and growth suppression activity of DLC-1. The Journal of cell biology 134 17190795
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
2004 Restoration of DLC-1 gene expression induces apoptosis and inhibits both cell growth and tumorigenicity in human hepatocellular carcinoma cells. Oncogene 124 14647417
2008 DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms. Molecular carcinogenesis 116 17932950
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
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
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 102 10213508
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2003 Transcriptional silencing of the DLC-1 tumor suppressor gene by epigenetic mechanism in gastric cancer cells. Oncogene 100 12813468
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
2006 Interaction of deleted in liver cancer 1 with tensin2 in caveolae and implications in tumor suppression. Cancer research 92 16951145
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
2007 The neutrophil-activating protein of Helicobacter pylori (HP-NAP) as an immune modulating agent. FEMS immunology and medical microbiology 84 17521355
2006 Aberrant methylation and deacetylation of deleted in liver cancer-1 gene in prostate cancer: potential clinical applications. Clinical cancer research : an official journal of the American Association for Cancer Research 82 16533763
2000 Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 81 11214970
2009 The Tensin-3 protein, including its SH2 domain, is phosphorylated by Src and contributes to tumorigenesis and metastasis. Cancer cell 80 19732724
2015 MicroRNA-106b promotes colorectal cancer cell migration and invasion by directly targeting DLC1. Journal of experimental & clinical cancer research : CR 73 26223867
2015 Developmental validation of the Quantifiler(®) HP and Trio Kits for human DNA quantification in forensic samples. Forensic science international. Genetics 71 26774100
2010 MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes. Hepatology (Baltimore, Md.) 71 20967756
2008 DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling. Journal of cell science 67 19066281
2016 LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex. Structure (London, England : 1993) 62 27265849
2018 Mechanotransduction in talin through the interaction of the R8 domain with DLC1. PLoS biology 55 30028837
2008 Deleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma. PloS one 55 18648664
2018 Resveratrol promotes oxidative stress to drive DLC1 mediated cellular senescence in cancer cells. Experimental cell research 54 29964052
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
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
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
2009 The immune modulating activity of the Helicobacter pylori HP-NAP: Friend or foe? Toxicon : official journal of the International Society on Toxinology 46 19818802
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 45 26401016
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
2003 The neutrophil-activating protein of Helicobacter pylori (HP-NAP) activates the MAPK pathway in human neutrophils. European journal of immunology 42 12672049
2016 DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers. Oncotarget 41 27174913
2006 Aberrant methylation of the 8p22 tumor suppressor gene DLC1 in renal cell carcinoma. Cancer letters 39 17029774
2016 Curcumin inhibits growth of human breast cancer cells through demethylation of DLC1 promoter. Molecular and cellular biochemistry 38 27830358
2009 Simultaneous loss of the DLC1 and PTEN tumor suppressors enhances breast cancer cell migration. Experimental cell research 38 19482022
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
2017 Receptor tyrosine kinase activation of RhoA is mediated by AKT phosphorylation of DLC1. The Journal of cell biology 35 29114068
2015 MicroRNA-141 regulates the tumour suppressor DLC1 in colorectal cancer. Neoplasma 34 26278151
2020 DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis. Journal of cell science 33 31964713
2016 Pathological and immunological characteristics of piglets infected experimentally with a HP-PRRSV TJ strain. BMC veterinary research 33 27733150
2001 Neutrophil-activating protein (HP-NAP) versus ferritin (Pfr): comparison of synthesis in Helicobacter pylori. FEMS microbiology letters 33 11356582
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
2000 Sequence variants of DLC1 in colorectal and ovarian tumours. Human mutation 32 10649492
2021 HP-β-CD for the formulation of IgG and Ig-based biotherapeutics. International journal of pharmaceutics 31 33775727
2016 HP-β-cyclodextrin as an inhibitor of amyloid-β aggregation and toxicity. Physical chemistry chemical physics : PCCP 31 27405335
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
2009 DLC1 activation requires lipid interaction through a polybasic region preceding the RhoGAP domain. Molecular biology of the cell 31 19710422
1992 Haptoglobin subtypes in Norway and a review of HP subtypes in various populations. Human heredity 31 1572675
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
2019 A tumor suppressor DLC1: The functions and signal pathways. Journal of cellular physiology 27 31773748
2023 Co-encapsulation of curcumin and quercetin with zein/HP-β-CD conjugates to enhance environmental resistance and antioxidant activity. NPJ science of food 25 37316567
2021 The parasite cytokine mimic Hp-TGM potently replicates the regulatory effects of TGF-β on murine CD4+ T cells. Immunology and cell biology 25 33988885
2019 Characterization of a polysaccharide HP-02 from Honeysuckle flowers and its immunoregulatory and anti-Aeromonas hydrophila effects in Cyprinus carpio L. International journal of biological macromolecules 25 31398403
2019 HP-1 inhibits the progression of ccRCC and enhances sunitinib therapeutic effects by suppressing EMT. Carbohydrate polymers 25 31427001
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 23 33171789
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
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
1997 PI, GC, HP, and TF serum protein polymorphisms in Siena, Tuscany, Italy, with a review of data for Italy. American journal of human biology : the official journal of the Human Biology Council 23 28561430
1981 Gc, Tf, Hp subtype and alpha 1-antitrypsin polymorphisms in a Pygmy Bi-Aka sample. Human heredity 23 6973533
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
2022 Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions. Food & function 21 35234761
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
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
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
2010 Haptoglobin (HP) polymorphisms and human longevity: a cross-sectional association study in a Central Italy population. Clinica chimica acta; international journal of clinical chemistry 19 21147083
2022 Suppression of airway allergic eosinophilia by Hp-TGM, a helminth mimic of TGF-β. Immunology 18 35758054
2020 Cancer-Associated Point Mutations in the DLC1 Tumor Suppressor and Other Rho-GAPs Occur Frequently and Are Associated with Decreased Function. Cancer research 18 32606003
2019 MDT-28/PLIN-1 mediates lipid droplet-microtubule interaction via DLC-1 in Caenorhabditis elegans. Scientific reports 18 31624276
2017 Asymmetric localization of DLC1 defines avian trunk neural crest polarity for directional delamination and migration. Nature communications 18 29084958
2019 Preparation and Characterisation of Polyphenol-HP-β-Cyclodextrin Inclusion Complex that Protects Lamb Tripe Protein against Oxidation. Molecules (Basel, Switzerland) 17 31817887
2014 Uncovering the rare variants of DLC1 isoform 1 and their functional effects in a Chinese sporadic congenital heart disease cohort. PloS one 17 24587289
2010 The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation. Experimental cell research 17 21087603
2008 Identification of the deleted in liver cancer 1 gene, DLC1, as a candidate meningioma tumor suppressor. Neurosurgery 17 18981889
2007 VacA and HP-NAP, Ying and Yang of Helicobacter pylori-associated gastric inflammation. Clinica chimica acta; international journal of clinical chemistry 17 17368441
2005 Structure-approximating inverse protein folding problem in the 2D HP model. Journal of computational biology : a journal of computational molecular cell biology 17 16379538
2023 Resveratrol induces DNA damage-mediated cancer cell senescence through the DLC1-DYRK1A-EGFR axis. Food & function 16 36651299
2023 Recombination and Mutation in a New HP-PRRSV Strain (SD2020) from China. Viruses 16 36680205
2017 Downregulation of microRNA-301a inhibited proliferation, migration and invasion of non-small cell lung cancer by directly targeting DLC1. Oncology letters 16 29113240
2014 Unique epitopes recognized by monoclonal antibodies against HP-PRRSV: deep understanding of antigenic structure and virus-antibody interaction. PloS one 16 25360600
2014 Cooperation of DLC1 and CDK6 affects breast cancer clinical outcome. G3 (Bethesda, Md.) 16 25425654
2021 Inhibition of cytoplasmic EZH2 induces antitumor activity through stabilization of the DLC1 tumor suppressor protein. Nature communications 15 34862367
2020 Nuclear DLC1 exerts oncogenic function through association with FOXK1 for cooperative activation of MMP9 expression in melanoma. Oncogene 15 32214200
2020 Aspartic acid at residue 185 modulates the capacity of HP-PRRSV nsp4 to antagonize IFN-I expression. Virology 15 32452419
2013 Promoter hypermethylation along with LOH, but not mutation, contributes to inactivation of DLC-1 in nasopharyngeal carcinoma. Molecular carcinogenesis 15 23908159
2012 Downregulation of DLC-1 gene by promoter methylation during primary colorectal cancer progression. BioMed research international 15 23509688
2010 DLC-1 as a modulator of proliferation, apoptosis and migration in Burkitt's lymphoma cells. Molecular biology reports 15 20882354
2008 Transcriptional induction of DLC-1 gene through Sp1 sites by histone deacetylase inhibitors in gastric cancer cells. Experimental & molecular medicine 15 19116449
2024 Interaction of zein/HP-β-CD nanoparticles with digestive enzymes: Enhancing curcumin bioavailability. Food chemistry 14 39126939