DLC1

Summary

DLC1 (DLC1 Rho GTPase activating protein, HGNC:2897) is a protein-coding gene on chromosome 8p22, encoding Rho GTPase-activating protein 7 (Q96QB1). Functions as a GTPase-activating protein for the small GTPases RHOA, RHOB, RHOC and CDC42, terminating their downstream signaling.

This gene encodes a GTPase-activating protein (GAP) that is a member of the rhoGAP family of proteins which play a role in the regulation of small GTP-binding proteins. GAP family proteins participate in signaling pathways that regulate cell processes involved in cytoskeletal changes. This gene functions as a tumor suppressor gene in a number of common cancers, including prostate, lung, colorectal, and breast cancers. Multiple transcript variants due to alternative promoters and alternative splicing have been found for this gene.

Source: NCBI Gene 10395 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 53
• Clinical variants (ClinVar): 930 total — 2 pathogenic
• MANE Select transcript: NM_182643

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2897
Approved symbol	DLC1
Name	DLC1 Rho GTPase activating protein
Location	8p22
Locus type	gene with protein product
Status	Approved
Aliases	HP, ARHGAP7, STARD12, DLC-1, p122-RhoGAP
Ensembl gene	ENSG00000164741
Ensembl biotype	protein_coding
OMIM	604258
Entrez	10395

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 11 protein_coding, 7 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000276297, ENST00000316609, ENST00000358919, ENST00000503161, ENST00000506171, ENST00000509922, ENST00000510250, ENST00000510318, ENST00000511869, ENST00000512044, ENST00000513883, ENST00000515225, ENST00000517333, ENST00000517868, ENST00000520226, ENST00000521730, ENST00000529018, ENST00000631382, ENST00000941271, ENST00000941272

RefSeq mRNA: 25 — MANE Select: NM_182643 NM_001164271, NM_001316668, NM_001348081, NM_001348082, NM_001348083, NM_001348084, NM_001413124, NM_001413125, NM_001413126, NM_001413127, NM_001413128, NM_001413129, NM_001413130, NM_001413131, NM_001413132, NM_001413133, NM_001413135, NM_001413136, NM_001413137, NM_001413138, NM_001413139, NM_001413140, NM_006094, NM_024767, NM_182643

CCDS: CCDS55201, CCDS5989, CCDS5990, CCDS5991, CCDS83253

Canonical transcript exons

ENST00000276297 — 18 exons

Exon	Start	End
ENSE00001015479	13393553	13393693
ENSE00001087057	13099347	13100770
ENSE00001087081	13305269	13305302
ENSE00001189213	13514602	13514851
ENSE00001216909	13083361	13085931
ENSE00001388926	13499049	13500196
ENSE00003303243	13401470	13401619
ENSE00003460075	13095086	13095245
ENSE00003502155	13091318	13091432
ENSE00003504743	13086290	13086463
ENSE00003522459	13110742	13110823
ENSE00003558013	13098399	13098575
ENSE00003613956	13088487	13088704
ENSE00003616232	13115586	13115657
ENSE00003617873	13094759	13094957
ENSE00003620503	13090252	13090470
ENSE00003662619	13102790	13102853
ENSE00003683998	13092612	13092825

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 98.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.0200 / max 1913.8144, expressed in 1614 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91920	39.4897	1578
91925	3.7841	897
91919	2.4945	1083
91942	1.4007	543
91926	1.3638	673
91949	1.3585	121
91929	0.7554	444
91939	0.6200	315
91916	0.5369	292
91944	0.4524	259

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.54	gold quality
lower lobe of lung	UBERON:0008949	98.23	gold quality
sural nerve	UBERON:0015488	97.02	gold quality
calcaneal tendon	UBERON:0003701	96.08	gold quality
omental fat pad	UBERON:0010414	95.89	gold quality
peritoneum	UBERON:0002358	95.88	gold quality
pericardium	UBERON:0002407	95.86	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.75	gold quality
upper lobe of lung	UBERON:0008948	95.64	gold quality
upper lobe of left lung	UBERON:0008952	95.54	gold quality
visceral pleura	UBERON:0002401	95.47	gold quality
synovial joint	UBERON:0002217	94.88	gold quality
colonic epithelium	UBERON:0000397	94.62	gold quality
adipose tissue	UBERON:0001013	94.34	gold quality
tendon	UBERON:0000043	94.24	gold quality
connective tissue	UBERON:0002384	94.10	gold quality
right lung	UBERON:0002167	93.63	gold quality
vena cava	UBERON:0004087	93.41	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.28	gold quality
parietal pleura	UBERON:0002400	93.16	gold quality
tendon of biceps brachii	UBERON:0008188	93.03	gold quality
heart right ventricle	UBERON:0002080	92.99	gold quality
vein	UBERON:0001638	92.77	gold quality
pleura	UBERON:0000977	92.70	gold quality
saphenous vein	UBERON:0007318	92.55	gold quality
nerve	UBERON:0001021	92.40	gold quality
tibial nerve	UBERON:0001323	92.40	gold quality
stromal cell of endometrium	CL:0002255	92.21	gold quality
corpus callosum	UBERON:0002336	91.84	gold quality
mammary duct	UBERON:0001765	91.24	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	11885.43
E-ANND-2	yes	7257.87
E-GEOD-180759	yes	4421.28
E-MTAB-7008	yes	88.59
E-HCAD-25	yes	54.58
E-ANND-3	yes	24.21
E-CURD-119	yes	23.41
E-HCAD-35	yes	22.50
E-MTAB-9067	yes	13.04
E-CURD-112	yes	10.53
E-GEOD-130148	yes	8.26
E-MTAB-10553	yes	7.04
E-GEOD-137537	yes	6.86
E-MTAB-9801	yes	5.96
E-MTAB-10137	no	4.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

147 targeting DLC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-511-3P	99.99	68.85	1467
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-545-3P	99.95	70.74	2783

Literature-anchored findings (GeneRIF, showing 40)

• Genomic deletion of DLC-1 was observed in 40% of breast tumors, whereas reduced levels of DLC-1 mRNA were seen in 70% of breast, 70% of colon, 50% of prostate tumor cell lines.DLC-1 gene plays a role in breast cancer by acting as a tumor suppressor gene (PMID:12545165)
• Differences in promoter hypermethylation were seen in 12 hepatocellular carcinoma, breast, colon, and prostate tumor cell lines with aberrant DLC-1 expression. Hypermethylation abrogates the function of the DLC-1 gene in a subset of these cancers. (PMID:12645648)
• genomic deletion and promoter methylation primarily account for the altered expression and tumor suppressive inactivation of the DLC-1 gene (PMID:12792785)
• Methylation of the DLC-1 CpG island is not uncommon in gastric cancer. The transcriptional silencing of DLC-1, by epigenetic mechanism, may be involved in gastric carcinogenesis. (PMID:12813468)
• Transcriptional silencing by hypermethylation may contribute to the inactivation of the DLC-1 gene in hepatocellular carcinoma. (PMID:14633684)
• Dlc-1 protein is involved in hepatocarcinogenesis and has oncosuppressive activity in Hepatocellular carcinoma. (PMID:14647417)
• DLC-1 plays a role in non-small cell lung carcinoma by acting as a bona fide new tumor suppressor gene. (PMID:14661059)
• Hypermethylation is responsible for silencing of DLC-1 gene in a limited portion of breast cancers. (PMID:15201975)
• Loss of DCL-1 is associated with prostate carcinomas (PMID:16533763)
• Taken together, our results suggest that DLC-1 might be an NPC-related tumor suppressor gene affected by aberrant promoter methylation and gene deletion. (PMID:16680376)
• Down-regulation of DLC1 is associated with non-Hodgkin’s lymphoma (PMID:16774933)
• DLC1 appears to be a major tumor suppressor genes implicated in the pathogenesis of these tumors (PMID:16862168)
• DLC1 and tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization. (PMID:16951145)
• These results provide a novel mechanism whereby the SH2 domain of cten-mediated focal adhesion localization of DLC-1 plays an essential role in its tumor suppression activity. (PMID:17190795)
• Involved in signal transduction pathway regulating cell proliferation, cell morphology, and cell migration in liver cancers. (PMID:17292327)
• These analyses provide evidence for a possible link between morphological alterations, protein nuclear translocation and proapoptotic and anti-oncogenic activities of DLC1 in lung cancer. (PMID:17888903)
• Down regulation of DLC1 is associated with non-small cell lung cancer (PMID:17932950)
• DLC1 methylation is a frequent event in multiple lymphomagenesis and could serve as a tumor-specific biomarker for future lymphoma diagnosis. (PMID:17965626)
• Results suggest that the DLC-1 gene is associated with cell proliferation, migration and cell cycle distribution in a colon cancer cell line. (PMID:18288400)
• DLC1 polymorphism is not associated with nasopharynmgeal neoplasm risk in Chinese population. (PMID:18627284)
• DLC1 negatively regulates Rho/ROCK/MLC2 (PMID:18648664)
• expression of the amino-terminal domain of DLC-1 acts as a dominant negative and profoundly inhibits cell migration by displacing endogenous DLC-1 from focal adhesions (PMID:18786931)
• Mutations in DLC-1 may lead to loss of function and contribute to the tumorigenesis, and have revealed an allosteric regulation site for its RhoGAP activity. (PMID:18829524)
• antiproliferative effect of DLC1 in a hematological cancer (PMID:18923442)
• data show that DLC1 is critically involved in the control of Rho signaling and actin cytoskeleton remodeling and that its cellular loss is sufficient for the acquisition of a more migratory phenotype of breast cancer cells (PMID:18974116)
• The results suggest that DLC1 may function as a tumor suppressor gene in meningiomas. Furthermore, DLC1 promoter methylation does not appear to be responsible for the decreased DLC1 expression in these tumors. (PMID:18981889)
• Results show that phorbol-ester-induced activation of protein kinases C and D stimulates association of DLC1 with 14-3-3 adaptor proteins, inhibiting RhoGAP activity and blocking nucleocytoplasmic transfer. (PMID:19066281)
• These results demonstrated the requirement of specific Sp1 sites and dependence of Sp1 and p300 for TSA-mediated activation of DLC-1 promoter. (PMID:19116449)
• p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. (PMID:19151751)
• This finding reveals a novel contribution of the SAM-EF1A1 interaction as a potentially important GAP-independent modulation of cell migration by DLC1. (PMID:19158340)
• Focal adhesion-localization of START-GAP1/DLC1 is essential for cell motility and morphology. (PMID:19170769)
• DLC-1 is a tumor suppressor protein with RhoGAP activity and roles in regulation of the cytoskeleton and cell motility [review] (PMID:19221866)
• DLC-1 plays a crucial role in signal transduction pathway regulating the cell proliferation, migration, and carcinogenesis of human renal cell carcinoma (PMID:19380190)
• In addition to properly localizing focal adhesions and preserving RhoGAP activity, DLC1 interaction with tensin2 through this novel focal adhesion binding site contributes to the growth-suppressive activity of DLC1. (PMID:19440389)
• Results suggest that the concerted local inactivation of signaling pathways downstream of PTEN and DLC1, respectively, is required for the tight control of cell migration. (PMID:19482022)
• Results confirm the role of DLC1 gene as a tumor suppressor, which may be manifested by regulation of p21 and cyclinDl. (PMID:19667410)
• DLC1 binds to phosphatidylinositol-4,5-bisphosphate through a previously unrecognized polybasic region adjacent to its RhoGAP domain. PI(4,5)P(2)-containing membranes are shown to stimulate DLC1 GAP activity in vitro. (PMID:19710422)
• Our findings suggest that DLC1 genetic polymorphism or haplotype play a role in mediating the susceptibility to hepatitis B virus-related hepatocellular carcinoma (PMID:19766077)
• Results suggest that PP1alpha bound to tensin1 has effects in reducing migration and invasion that are not mediated through DLC-1, and show the importance of PP1alpha binding to tensin1 for the regulation of cell polarization, migration, and invasion. (PMID:19826001)
• DLC1 isoforms are differentially expressed in human tissues, have different epigenetic transcriptional regulations and are functionally different. (PMID:19874489)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlc1	ENSDARG00000079317
mus_musculus	Dlc1	ENSMUSG00000031523
rattus_norvegicus	Dlc1	ENSRNOG00000010780
caenorhabditis_elegans		WBGENE00001559

Paralogs (2): STARD8 (ENSG00000130052), STARD13 (ENSG00000133121)

Protein

Protein identifiers

Rho GTPase-activating protein 7 — Q96QB1 (reviewed: Q96QB1)

Alternative names: Deleted in liver cancer 1 protein, HP protein, Rho-type GTPase-activating protein 7, START domain-containing protein 12, StAR-related lipid transfer protein 12

All UniProt accessions (4): A0A0J9YWS8, E5RI70, Q96QB1, R4GMP5

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a GTPase-activating protein for the small GTPases RHOA, RHOB, RHOC and CDC42, terminating their downstream signaling. This induces morphological changes and detachment through cytoskeletal reorganization, playing a critical role in biological processes such as cell migration and proliferation. Also functions in vivo as an activator of the phospholipase PLCD1. Active DLC1 increases cell migration velocity but reduces directionality. Required for growth factor-induced epithelial cell migration; in resting cells, interacts with TNS3 while PTEN interacts with the p85 regulatory subunit of the PI3K kinase complex but growth factor stimulation induces phosphorylation of TNS3 and PTEN, causing them to change their binding preference so that PTEN interacts with DLC1 and TNS3 interacts with p85. The PTEN-DLC1 complex translocates to the posterior of migrating cells to activate RHOA while the TNS3-p85 complex translocates to the leading edge of migrating cells to promote RAC1 activation.

Subunit / interactions. Interacts with EF1A1, facilitates EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation and suppresses cell migration. Interacts with tensin TNS1 (via N-terminus); the interaction is decreased by phosphorylation of TNS1. Interacts with TNS3 and PTEN; in resting cells, interacts with TNS3 (via C2 tensin-type domain) but, following growth factor stimulation, TNS3 and PTEN are phosphorylated which leads to weakened interaction with TNS3 and enhanced interaction with PTEN. Interacts (via C-terminus) with tensin TNS4 (via SH2 domain); the interaction is independent of tyrosine phosphorylation of DLC1.

Subcellular location. Cytoplasm. Cell junction. Focal adhesion. Membrane.

Tissue specificity. Highest level of expression in the spleen, with rather lower levels in prostate, testis, ovary, small intestine and colon, but none in the thymus.

Domain organisation. The SAM domain mediates interaction with EF1A1, and functions as an autoinhibitory regulator of RhoGAP Activity. The polybasic cluster is required for activation and mediates binding to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P(2)) containing membranes.

Miscellaneous. Produced by alternative promoter usage. ubiquitously expressed, significantly down-regulated in multiple carcinoma cell lines.

Isoforms (6)

UniProt ID	Names	Canonical?
Q96QB1-2	2	yes
Q96QB1-1	1
Q96QB1-3	3
Q96QB1-4	4
Q96QB1-5	5
Q96QB1-6	6, i-4

RefSeq proteins (25): NP_001157743, NP_001303597, NP_001335010, NP_001335011, NP_001335012, NP_001335013, NP_001400053, NP_001400054, NP_001400055, NP_001400056, NP_001400057, NP_001400058, NP_001400059, NP_001400060, NP_001400061, NP_001400062, NP_001400064, NP_001400065, NP_001400066, NP_001400067, NP_001400068, NP_001400069, NP_006085, NP_079043, NP_872584* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR001660	SAM	Domain
IPR002913	START_lipid-bd_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR023393	START-like_dom_sf	Homologous_superfamily

Pfam: PF00620, PF01852, PF07647

UniProt features (83 total): helix 16, sequence variant 13, region of interest 9, compositionally biased region 9, splice variant 9, sequence conflict 6, mutagenesis site 5, modified residue 4, turn 4, domain 3, strand 3, chain 1, site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5FZT	X-RAY DIFFRACTION	2.1
3KUQ	X-RAY DIFFRACTION	2.3
7TPB	X-RAY DIFFRACTION	3.2
2DKY	SOLUTION NMR
2GYT	SOLUTION NMR
2KAP	SOLUTION NMR
2LOZ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96QB1-F1	56.62	0.20

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1114 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (4): 523, 526, 566, 757

Mutagenesis-validated functional residues (5):

Position	Phenotype
475	abolishes interaction with ef1a1.
476	abolishes interaction with ef1a1.
877	abolishes interaction with tns4 and results in diffuse cytoplasmic localization.
879	unable to displace endogenous dlc1 from focal adhesions. abolishes interaction with tns4 and results in diffuse cytoplas
1114	no catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle

MSigDB gene sets: 467 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, MODULE_255, PEREZ_TP63_TARGETS, ATACCTC_MIR202, GOBP_FOCAL_ADHESION_ASSEMBLY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION

GO Biological Process (16): neural tube closure (GO:0001843), heart morphogenesis (GO:0003007), negative regulation of cell population proliferation (GO:0008285), hindbrain morphogenesis (GO:0021575), actin cytoskeleton organization (GO:0030036), negative regulation of cell migration (GO:0030336), forebrain development (GO:0030900), regulation of Rho protein signal transduction (GO:0035023), negative regulation of Rho protein signal transduction (GO:0035024), intracellular signal transduction (GO:0035556), focal adhesion assembly (GO:0048041), regulation of small GTPase mediated signal transduction (GO:0051056), negative regulation of stress fiber assembly (GO:0051497), negative regulation of focal adhesion assembly (GO:0051895), positive regulation of execution phase of apoptosis (GO:1900119), signal transduction (GO:0007165)

GO Molecular Function (4): GTPase activator activity (GO:0005096), lipid binding (GO:0008289), SH2 domain binding (GO:0042169), protein binding (GO:0005515)

GO Cellular Component (11): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), caveola (GO:0005901), focal adhesion (GO:0005925), cortical actin cytoskeleton (GO:0030864), ruffle membrane (GO:0032587), membrane raft (GO:0045121), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	6

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
Rho protein signal transduction	2
intracellular anatomical structure	2
binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
primary neural tube formation	1
tube closure	1
heart development	1
animal organ morphogenesis	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
anatomical structure morphogenesis	1
hindbrain development	1
cytoskeleton organization	1
actin filament-based process	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
brain development	1
anatomical structure development	1
regulation of small GTPase mediated signal transduction	1
regulation of Rho protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
signal transduction	1
cell-substrate junction assembly	1
cell-matrix adhesion	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
negative regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
negative regulation of cell-matrix adhesion	1
focal adhesion assembly	1
regulation of focal adhesion assembly	1
negative regulation of cell-substrate junction organization	1
negative regulation of cell junction assembly	1
positive regulation of apoptotic process	1
execution phase of apoptosis	1

Protein interactions and networks

STRING

1005 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLC1	PLCD1	P51178	912
DLC1	TNS2	Q63HR2	904
DLC1	RHOA	P06749	727
DLC1	TLN2	Q9Y4G6	686
DLC1	TLN1	Q9Y490	676
DLC1	TNS1	Q9HBL0	640
DLC1	PXN	P49023	638
DLC1	TNS4	Q8IZW8	621
DLC1	APBB1IP	Q7Z5R6	599
DLC1	HP	P00737	571
DLC1	CDC42	P21181	568
DLC1	AKT1	P31749	566
DLC1	CAV1	Q03135	554
DLC1	SRC	P12931	526
DLC1	TNS3	Q68CZ2	511

IntAct

47 interactions, top by confidence:

A	B	Type	Score
DLC1	RASA1	psi-mi:“MI:0915”(physical association)	0.710
RASA1	DLC1	psi-mi:“MI:0915”(physical association)	0.710
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
Stard13	DLC1	psi-mi:“MI:0915”(physical association)	0.500
TNS1	DLC1	psi-mi:“MI:0915”(physical association)	0.400
DLC1	UTP6	psi-mi:“MI:0915”(physical association)	0.400
DLC1	TNS3	psi-mi:“MI:0915”(physical association)	0.400
ACOT7	DLC1	psi-mi:“MI:0915”(physical association)	0.370
PFKM	DLC1	psi-mi:“MI:0915”(physical association)	0.370
DLC1	PKM	psi-mi:“MI:0915”(physical association)	0.370
RANGAP1	DLC1	psi-mi:“MI:0915”(physical association)	0.370
DLC1	TMEM129	psi-mi:“MI:0915”(physical association)	0.370
DLC1	USP4	psi-mi:“MI:0915”(physical association)	0.370
BAAT	DLC1	psi-mi:“MI:0915”(physical association)	0.370
DLC1	TRMO	psi-mi:“MI:0915”(physical association)	0.370
AOPEP	DLC1	psi-mi:“MI:0915”(physical association)	0.370
CDC14B	DLC1	psi-mi:“MI:0915”(physical association)	0.370
DLC1	CORO2A	psi-mi:“MI:0915”(physical association)	0.370
DLC1	CTSV	psi-mi:“MI:0915”(physical association)	0.370
DLC1	FANCC	psi-mi:“MI:0915”(physical association)	0.370
DLC1	FBP2	psi-mi:“MI:0915”(physical association)	0.370
DLC1	HEMGN	psi-mi:“MI:0915”(physical association)	0.370
DLC1	HSD17B3	psi-mi:“MI:0915”(physical association)	0.370
DLC1	CCDC180	psi-mi:“MI:0915”(physical association)	0.370
DLC1	MAPKAPK3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (76): DLC1 (Biochemical Activity), DLC1 (Biochemical Activity), WWC2 (Affinity Capture-Western), WWC3 (Affinity Capture-Western), WWC1 (Affinity Capture-Western), DLC1 (Synthetic Lethality), TENC1 (Reconstituted Complex), CAV1 (Affinity Capture-Western), DLC1 (Affinity Capture-Western), LACC1 (Affinity Capture-MS), FEM1B (Affinity Capture-MS), C17orf75 (Affinity Capture-MS), PTEN (Affinity Capture-Western), PTEN (Reconstituted Complex), DLC1 (Affinity Capture-Western)

ESM2 similar proteins: A2A995, A2ALU4, A4IGN8, A6NMK8, D3ZUI5, E1C2Q8, F1QGH6, O54931, O75128, O75363, O75410, O95425, P24275, P24588, P51827, Q1LWM5, Q1RMS0, Q1W617, Q3UHI0, Q3UMF0, Q3ZB98, Q499V8, Q53SF7, Q5JR59, Q5NBX1, Q5VWT5, Q5ZJ26, Q62394, Q66KC9, Q673G8, Q69ZL1, Q6GQV1, Q6INC4, Q6QZN6, Q6WKZ4, Q6Y685, Q7TP36, Q7TS75, Q80YN3, Q8BI29

Diamond homologs: A0A0G2JTR4, A1A4S6, A2AB59, A2RUV4, A4IF90, A4II46, A6NI28, A6QNS3, A7E300, A7YY57, B2RQE8, B5DFQ4, B9VTT2, D3ZZN9, E9Q6X9, F1LQX4, O14559, O60890, O74360, O94466, P0CAX5, P11274, P15882, P30337, P34288, P40809, P46941, P52757, P97393, Q03070, Q07960, Q08DP6, Q12979, Q13017, Q13459, Q17QN0, Q17R89, Q53QZ3, Q54FG5, Q54TH9

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
PRKD1	down-regulates	DLC1	phosphorylation
DLC1	“down-regulates activity”	MYH9	binding
CDK5	“up-regulates activity”	DLC1	phosphorylation
AKT	unknown	DLC1	phosphorylation
AKT1	unknown	DLC1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

930 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	615
Likely benign	164
Benign	105

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
15899	NG_012651.1:g.=	Pathogenic
5699	NM_182643.3(DLC1):c.2875A>G (p.Thr959Ala)	Pathogenic

SpliceAI

796 predictions. Top by Δscore:

Variant	Effect	Δscore
16:72056155:CTGCA:C	acceptor_loss	1.0000
16:72056156:TGCA:T	acceptor_loss	1.0000
16:72056157:GCA:G	acceptor_loss	1.0000
16:72056158:CAGTG:C	acceptor_loss	1.0000
16:72056159:A:AG	acceptor_gain	1.0000
16:72056159:AGT:A	acceptor_gain	1.0000
16:72056160:G:GT	acceptor_gain	1.0000
16:72056160:GT:G	acceptor_gain	1.0000
16:72056160:GTG:G	acceptor_gain	1.0000
16:72056160:GTGC:G	acceptor_gain	1.0000
16:72056160:GTGCC:G	acceptor_gain	1.0000
16:72056527:CAGAT:C	acceptor_loss	1.0000
16:72056528:A:AC	acceptor_loss	1.0000
16:72056528:A:AG	acceptor_gain	1.0000
16:72056528:AGAT:A	acceptor_gain	1.0000
16:72056529:G:GG	acceptor_gain	1.0000
16:72056529:GA:G	acceptor_gain	1.0000
16:72056529:GAT:G	acceptor_gain	1.0000
16:72056529:GATG:G	acceptor_gain	1.0000
16:72056529:GATGA:G	acceptor_gain	1.0000
16:72056594:GT:G	donor_gain	1.0000
16:72056628:GATG:G	donor_gain	1.0000
16:72056630:TGGT:T	donor_loss	1.0000
16:72056632:G:GG	donor_gain	1.0000
16:72056632:GT:G	donor_loss	1.0000
16:72056633:T:A	donor_loss	1.0000
16:72058249:T:TA	acceptor_gain	1.0000
16:72058250:GCAG:G	acceptor_loss	1.0000
16:72058251:CA:C	acceptor_loss	1.0000
16:72058252:A:AG	acceptor_gain	1.0000

AlphaMissense

10138 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:13091355:A:G	L1273P	1.000
8:13091367:G:T	A1269D	1.000
8:13092668:G:C	C1228W	1.000
8:13092669:C:T	C1228Y	1.000
8:13092670:A:G	C1228R	1.000
8:13092675:G:T	A1226D	1.000
8:13092678:A:G	L1225P	1.000
8:13092680:G:C	N1224K	1.000
8:13092680:G:T	N1224K	1.000
8:13092693:A:C	M1220R	1.000
8:13092693:A:G	M1220T	1.000
8:13092720:A:T	V1211D	1.000
8:13092729:A:G	L1208P	1.000
8:13094821:C:G	R1155P	1.000
8:13094832:C:A	K1151N	1.000
8:13094832:C:G	K1151N	1.000
8:13094834:T:C	K1151E	1.000
8:13094836:A:G	L1150P	1.000
8:13094842:T:A	D1148V	1.000
8:13094842:T:C	D1148G	1.000
8:13094842:T:G	D1148A	1.000
8:13094843:C:G	D1148H	1.000
8:13094845:G:T	A1147E	1.000
8:13094846:C:G	A1147P	1.000
8:13094851:T:C	D1145G	1.000
8:13094852:C:G	D1145H	1.000
8:13094908:C:G	R1126P	1.000
8:13094909:G:T	R1126S	1.000
8:13094911:A:G	L1125P	1.000
8:13094920:A:G	I1122T	1.000

dbSNP variants (sampled 300 via entrez): RS1000001983 (8:13466576 A>G,T), RS1000005118 (8:13413805 C>A,T), RS1000010748 (8:13331345 A>G), RS1000010820 (8:13340463 A>T), RS1000013266 (8:13557868 T>C), RS1000019625 (8:13208753 C>A,G), RS1000022785 (8:13358100 C>A,G), RS1000027432 (8:13493928 T>C), RS1000031577 (8:13441345 G>A), RS1000032530 (8:13268357 C>A,G), RS1000032940 (8:13278151 G>A,C,T), RS1000033805 (8:13526120 G>A,T), RS1000034976 (8:13466398 C>G), RS1000041133 (8:13217953 C>T), RS1000047482 (8:13439769 T>C)

Disease associations

OMIM: gene MIM:604258 | disease phenotypes: MIM:114500, MIM:614081

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome	Strong	Autosomal recessive
congenital heart defects, multiple types	Limited	Autosomal dominant
colorectal cancer	No Known Disease Relationship	Unknown

Mondo (8): colorectal cancer (MONDO:0005575), anhaptoglobinemia (MONDO:0013564), breast ductal adenocarcinoma (MONDO:0005590), neural tube defect (MONDO:0018075), primary amenorrhea (MONDO:1060208), colon carcinoma (MONDO:0002032), congenital heart defects, multiple types (MONDO:0000119), nephrotic syndrome (MONDO:0005377)

Orphanet (3): Neural tube defect (Orphanet:3388), Spina bifida and other spinal dysraphisms (Orphanet:823), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

53 associations (top):

Study	Trait	p-value
GCST000759_13	LDL cholesterol	2.000000e-22
GCST000760_22	Cholesterol, total	3.000000e-24
GCST001435_1	Haptoglobin levels	8.000000e-59
GCST001569_4	Bipolar disorder	5.000000e-06
GCST001639_4	Metabolite levels	1.000000e-36
GCST001762_945	Obesity-related traits	4.000000e-06
GCST002304_12	Fractional exhaled nitric oxide (childhood)	1.000000e-12
GCST002304_23	Fractional exhaled nitric oxide (childhood)	9.000000e-07
GCST002896_11	Cholesterol, total	3.000000e-23
GCST002898_10	LDL cholesterol	2.000000e-20
GCST002942_2	Percentage gas trapping	6.000000e-07
GCST002945_49	Emphysema imaging phenotypes	1.000000e-08
GCST002945_51	Emphysema imaging phenotypes	6.000000e-10
GCST003815_26	Late-onset Alzheimer’s disease	4.000000e-06
GCST003999_25	Nose size	4.000000e-07
GCST004735_7	Epstein-Barr virus copy number in lymphoblastoid cell lines	7.000000e-06
GCST004736_1	Familial hepatitis B virus-related hepatocellular carcinoma	3.000000e-07
GCST004744_44	Lung adenocarcinoma	6.000000e-06
GCST004865_38	Itch intensity from mosquito bite adjusted by bite size	3.000000e-06
GCST005051_18	Obstructive sleep apnea trait (apnea hypopnea index)	2.000000e-07
GCST005580_195	Intraocular pressure	4.000000e-08
GCST005807_1	Urinary haptoglobin levels in type 2 diabetes	1.000000e-60
GCST005808_1	Plasma haptoglobin levels in type 2 diabetes	7.000000e-12
GCST006004_19	Low density lipoprotein cholesterol levels	7.000000e-16
GCST006034_2	Total cholesterol levels	3.000000e-31
GCST006218_96	Erosive tooth wear (severe vs non-severe)	7.000000e-07
GCST006226_21	Erosive tooth wear (severe vs none or mild)	5.000000e-06
GCST006916_5	Attention deficit hyperactivity disorder	4.000000e-07
GCST006979_452	Heel bone mineral density	1.000000e-12
GCST007565_14	Morning person	2.000000e-15

EFO canonical traits (28, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004640	haptoglobin measurement
EFO:0004723	coronary artery calcification
EFO:0005536	nitric oxide exhalation measurement
EFO:0007628	gas trapping measurement
EFO:0007626	emphysema imaging measurement
EFO:1001870	late-onset Alzheimers disease
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0007817	sleep apnea measurement
EFO:0004695	intraocular pressure measurement
EFO:0009270	heel bone mineral density
EFO:0008328	chronotype measurement
EFO:0004343	waist-hip ratio
EFO:0005112	gestational age
EFO:0010347	cholesteryl ester 20:3 measurement
EFO:0010506	kynurenic acid measurement
EFO:0006527	smoking status measurement
EFO:0007796	parental longevity
EFO:0004509	hemoglobin measurement
EFO:0009262	nicotine dependence symptom count
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004462	PR interval
EFO:0007874	gut microbiome measurement
EFO:0006925	lipoprotein A measurement
EFO:0004980	appendicular lean mass
EFO:0007984	platelet component distribution width

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
D009436	Neural Tube Defects	C10.500.680; C16.131.666.680

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	7
Estradiol	increases expression, affects expression, affects cotreatment, decreases expression, decreases reaction	4
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	decreases methylation, affects cotreatment, affects expression	2
sodium arsenite	increases expression, decreases expression, increases abundance	2
mercuric bromide	affects cotreatment, increases expression	2
Panobinostat	increases expression, affects cotreatment	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Doxorubicin	affects response to substance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	increases methylation	2
Particulate Matter	increases abundance, increases expression, affects expression, increases reaction	2
FR900359	increases phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, increases activity, increases expression	1
methylselenic acid	increases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
cupric oxide	decreases expression	1
1-nitropyrene	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
ciglitazone	affects binding, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
dorsomorphin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	PHASE4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer