ARHGEF11

Summary

ARHGEF11 (Rho guanine nucleotide exchange factor 11, HGNC:14580) is a protein-coding gene on chromosome 1q23.1, encoding Rho guanine nucleotide exchange factor 11 (O15085). May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13).

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. A similar protein in rat interacts with glutamate transporter EAAT4 and modulates its glutamate transport activity. Expression of the rat protein induces the reorganization of the actin cytoskeleton and its overexpression induces the formation of membrane ruffling and filopodia. Two alternative transcripts encoding different isoforms have been described.

Source: NCBI Gene 9826 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 224 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_198236

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14580
Approved symbol	ARHGEF11
Name	Rho guanine nucleotide exchange factor 11
Location	1q23.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0380, GTRAP48, PDZ-RHOGEF
Ensembl gene	ENSG00000132694
Ensembl biotype	protein_coding
OMIM	605708
Entrez	9826

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 17 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000361409, ENST00000368194, ENST00000461678, ENST00000483682, ENST00000486670, ENST00000487682, ENST00000492592, ENST00000715594, ENST00000715595, ENST00000935551, ENST00000935552, ENST00000935553, ENST00000935554, ENST00000935555, ENST00000935556, ENST00000935557, ENST00000935558, ENST00000956711, ENST00000956712, ENST00000956713, ENST00000956714, ENST00000956715

RefSeq mRNA: 4 — MANE Select: NM_198236 NM_001377418, NM_001377419, NM_014784, NM_198236

CCDS: CCDS1162, CCDS1163

Canonical transcript exons

ENST00000368194 — 41 exons

Exon	Start	End
ENSE00000904836	156984339	156984437
ENSE00000904837	156980437	156980486
ENSE00000904838	156979229	156979286
ENSE00000904839	156978204	156978382
ENSE00000904840	156976983	156977054
ENSE00000904843	156967987	156968124
ENSE00000904853	156948319	156948498
ENSE00000904855	156947769	156947956
ENSE00000904856	156947304	156947450
ENSE00000904859	156946045	156946162
ENSE00000904866	156940207	156940425
ENSE00001054866	156951573	156951699
ENSE00001074420	156955703	156955799
ENSE00001195407	156948181	156948228
ENSE00001195422	156954892	156954921
ENSE00001253771	156939548	156939910
ENSE00001253778	156945019	156945197
ENSE00001381605	156971697	156971816
ENSE00001436720	156986082	156986173
ENSE00001436755	157044299	157045742
ENSE00001920665	156934840	156936058
ENSE00003465716	156956420	156956564
ENSE00003484300	156941864	156941989
ENSE00003516514	156963203	156963304
ENSE00003517271	156958742	156958864
ENSE00003541825	156969282	156969358
ENSE00003557586	156946936	156947015
ENSE00003573297	156960418	156960460
ENSE00003573363	156946662	156946787
ENSE00003577048	156941372	156941433
ENSE00003593434	156938418	156938513
ENSE00003596568	156961677	156961775
ENSE00003597025	156969998	156970043
ENSE00003597738	156957792	156957815
ENSE00003611803	156959046	156959142
ENSE00003642987	156937249	156937496
ENSE00003643329	156963520	156963594
ENSE00003644928	156942690	156942780
ENSE00003660406	156936816	156937005
ENSE00003660751	156943935	156944102
ENSE00003679518	156944358	156944433

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 93.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.9792 / max 256.9575, expressed in 1781 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15244	10.7253	1696
15245	1.7041	895
15246	1.2117	573
15241	0.9784	214
15243	0.9013	218
15242	0.3848	166
15240	0.0736	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	93.03	gold quality
left testis	UBERON:0004533	92.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.04	gold quality
testis	UBERON:0000473	91.68	gold quality
blood	UBERON:0000178	91.38	gold quality
cerebellum	UBERON:0002037	91.38	gold quality
cerebellar hemisphere	UBERON:0002245	91.34	gold quality
cortical plate	UBERON:0005343	91.34	gold quality
cerebellar cortex	UBERON:0002129	91.32	gold quality
monocyte	CL:0000576	90.99	gold quality
leukocyte	CL:0000738	90.86	gold quality
right frontal lobe	UBERON:0002810	90.77	gold quality
superior frontal gyrus	UBERON:0002661	90.59	gold quality
primary visual cortex	UBERON:0002436	90.52	gold quality
frontal cortex	UBERON:0001870	90.38	gold quality
sural nerve	UBERON:0015488	90.35	gold quality
prefrontal cortex	UBERON:0000451	90.06	gold quality
pituitary gland	UBERON:0000007	90.01	gold quality
mucosa of transverse colon	UBERON:0004991	89.72	gold quality
apex of heart	UBERON:0002098	89.51	gold quality
corpus callosum	UBERON:0002336	89.39	gold quality
right lobe of thyroid gland	UBERON:0001119	89.37	gold quality
adenohypophysis	UBERON:0002196	89.21	gold quality
right adrenal gland cortex	UBERON:0035827	89.08	gold quality
right adrenal gland	UBERON:0001233	89.01	gold quality
granulocyte	CL:0000094	88.83	gold quality
cerebral cortex	UBERON:0000956	88.71	gold quality
lower esophagus mucosa	UBERON:0035834	88.69	gold quality
transverse colon	UBERON:0001157	88.67	gold quality
fundus of stomach	UBERON:0001160	88.61	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting ARHGEF11, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811

Literature-anchored findings (GeneRIF, showing 29)

• Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho-GEF(LARG) and this protein. (PMID:12183458)
• PDZ-RhoGEF interacts directly with p21-activated kinase 4 to negatively regulate the activation of Rho (PMID:14625312)
• ARHGER11 is involved in the pathologic changes associated with decreased glutamatergic neurotransmission in schizophrenia (PMID:14684465)
• PDZ-RhoGEF interacts with the actin cytoskeleton (PMID:14742719)
• Data show that different rho guanine nucleotide exchange factors (rhoGEFs; p115rhoGEF, LARG and PDZrhoGEF) mediate downstream rho signaling by the thrombin and lysophosphatidic acid receptors. (PMID:15143072)
• This is the first epidemiological study to link PDZ-RhoGEF polymorphisms with cancer risk, specifically in Mexican Americans at risk for lung cancer. (PMID:16691626)
• Variation within ARHGEF11 nominally increases risk of type 2 diabetes, possibly as a result of increased insulin resistance. (PMID:17287471)
• Sequence variation in this gene may influence susceptibility to and risk of type II diabetes. (PMID:17369523)
• PDZRhoGEF (PRG), mediates RhoA-dependent responses and determines their spatial distribution in differentiated HL60 cells. (PMID:18086913)
• R1467H variant in the rho guanine nucleotide exchange factor 11 (ARHGEF11) is associated with impaired glucose tolerance and type 2 diabetes in German Caucasians. (PMID:18231709)
• the autoinhibition of PRG is caused largely by an interaction of a short negatively charged sequence motif, immediately upstream of the DH-domain. (PMID:19460155)
• The actin-binding domain of PDZ-RhoGEF, located between amino acids 561 and 585, directly binds to F-actin in vitro and could influence actin structure in a manner independent of its ability to activate RhoA. (PMID:19618964)
• PYK2 and PDZ-RhoGEF are necessary for angiotensin II-induced RhoA activation and for Ca(2+) signaling to RhoA. (PMID:19759375)
• The R1467H polymorphism of ARHGEF11 gene may contribute to susceptibility to type 2 diabetes mellitus and insulin resistance in a Chinese population. (PMID:21210224)
• Mechanistic insights into specificity, activity, and regulatory elements of the regulator of G-protein signaling (RGS)-containing Rho-specific guanine nucleotide exchange factors (GEFs) p115, PDZ-RhoGEF (PRG), and leukemia-associated RhoGEF (LARG). (PMID:21454492)
• analysis of molecular activation mechanism of the RhoA-specific guanine nucleotide exchange factor, PDZRhoGEF (PMID:21816819)
• Agonist-induced Ca2+ sensitization in smooth muscle: redundancy of Rho guanine nucleotide exchange factors (RhoGEFs) and response kinetics, a caged compound study. (PMID:24106280)
• Regulated localization is sufficient for hormonal control of regulator of G protein signaling homology Rho guanine nucleotide exchange factors (RH-RhoGEFs). (PMID:24855647)
• Results provide new evidence that ARHGEF11 may constitute a risk factor for schizophrenia (PMID:25319871)
• Data show that endothelin A receptor drives invadopodia function by direct interaction of beta-arrestin-1 (beta-arr1) with Rho guanine nucleotide exchange factor (GEF) 11 protein (PDZ-RhoGEF). (PMID:26522724)
• Two related guanine nucleotide exchange factors (GEFs), PDZ-RhoGEF and leukemia-associated RhoGEF (LARG), use their PDZ domains to bind class B plexins and play critical roles in signaling. (PMID:26627240)
• PAK4 (but not PAK1) mediates invadopodia maturation during melanoma invasion likely via inhibition of PDZ-RhoGEF. (PMID:27765920)
• SNPs associated with type 2 diabetes and obesity may also increase the risk of developing gestational diabetes mellitus (GDM) in the Chinese population. Among these SNPs, we report for the first time that rs945508 in ARHGEF11, rs10804591 in PLXND1 and rs10245353 in NFE2L3 were associated with GDM. (PMID:28554271)
• ARHGRF11 inhibited the insulin signaling pathway in placenta and may participate in fetal macrosomia in normal glucose tolerance pregnant women (PMID:29486856)
• PDZ-RhoGEF role in the glioblastoma cell invasion and survival.PDZ-RhoGEF is an effector of TROY signaling. (PMID:30219706)
• results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment. (PMID:30521495)
• Epigenetic alteration of Rho guanine nucleotide exchange Factor 11 (ARHGEF11) in cord blood samples in macrosomia exposed to intrauterine hyperglycemia. (PMID:30999786)
• Galphas directly drives PDZ-RhoGEF signaling to Cdc42. (PMID:33023908)
• ARHGEF11 promotes proliferation and epithelial-mesenchymal transition of hepatocellular carcinoma through activation of beta-catenin pathway. (PMID:33122451)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef11	ENSDARG00000052482
mus_musculus	Arhgef11	ENSMUSG00000041977
rattus_norvegicus	Arhgef11	ENSRNOG00000015026
drosophila_melanogaster	cyst	FBGN0032796
caenorhabditis_elegans	prhg-1	WBGENE00022391

Paralogs (8): PLEKHG6 (ENSG00000008323), ARHGEF1 (ENSG00000076928), ARHGEF18 (ENSG00000104880), ARHGEF2 (ENSG00000116584), ARHGEF3 (ENSG00000163947), NET1 (ENSG00000173848), ARHGEF12 (ENSG00000196914), ARHGEF28 (ENSG00000214944)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 11 — O15085 (reviewed: O15085)

Alternative names: PDZ-RhoGEF

All UniProt accessions (3): O15085, A0AAQ5BII7, A0AAQ5BIK5

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13. Involved in neurotrophin-induced neurite outgrowth.

Subunit / interactions. Interacts with GNA12 and GNA13 through the RGS domain. Interacts with RHOA, PLXNB1 and PLXNB2. Interacts with SLC1A6. Interacts (via DH domain) with GCSAM (via C-terminus). Found in a complex with ARHGEF11 and ARHGEF12; binding to ARHGEF11 and ARHGEF12 enhances CDC42 GEF activity of PLEKHG4B, and PLEKHG4B, in turn, inhibits ARHGEF11- and ARHGEF12-mediated RHOA activation.

Subcellular location. Cytoplasm. Membrane.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Phosphorylated by MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14). Ubiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex when previously phosphorylated by MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14), leading to its degradation, thereby restricting RhoA activity and facilitating growth cone spreading and neurite outgrowth.

Domain organisation. The poly-Pro region is essential for plasma membrane localization upon stimulation.

Isoforms (2)

UniProt ID	Names	Canonical?
O15085-1	1	yes
O15085-2	2

RefSeq proteins (4): NP_001364347, NP_001364348, NP_055599, NP_937879* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001478	PDZ	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015212	RGS-like_dom	Domain
IPR016137	RGS	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036305	RGS_sf	Homologous_superfamily
IPR037803	PRG_PH	Domain
IPR037889	PDZRhoGEF_RGS	Domain
IPR041020	PH_16	Domain
IPR044926	RGS_subdomain_2	Homologous_superfamily

Pfam: PF00595, PF00621, PF09128, PF17838

UniProt features (101 total): helix 29, modified residue 22, strand 20, region of interest 10, compositionally biased region 9, domain 4, sequence variant 2, turn 2, chain 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
1HTJ	X-RAY DIFFRACTION	2.2
5JHH	X-RAY DIFFRACTION	2.3
5TYT	X-RAY DIFFRACTION	2.4
1XCG	X-RAY DIFFRACTION	2.5
5JHG	X-RAY DIFFRACTION	2.5
3KZ1	X-RAY DIFFRACTION	2.7
3T06	X-RAY DIFFRACTION	2.84
5E6P	X-RAY DIFFRACTION	3.21
2DLS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15085-F1	60.63	0.28

Functional residue map

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

Post-translational modifications (22): 2, 14, 16, 35, 245, 251, 254, 255, 271, 556, 635, 663, 668, 672, 1155, 1295, 1300, 1457, 1458, 1462 …

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-416572	Sema4D induced cell migration and growth-cone collapse
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-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-373755	Semaphorin interactions
R-HSA-388396	GPCR downstream signalling
R-HSA-400685	Sema4D in semaphorin signaling
R-HSA-422475	Axon guidance
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 174 (showing top): BIOCARTA_RHO_PATHWAY, RRAGTTGT_UNKNOWN, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_GROWTH, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ESTABLISHMENT_OF_CELL_POLARITY, GOBP_MUSCLE_CONTRACTION, AACTTT_UNKNOWN, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GOBP_MUSCLE_SYSTEM_PROCESS, GOMF_SIGNALING_RECEPTOR_BINDING

GO Biological Process (8): regulation of cell growth (GO:0001558), striated muscle contraction (GO:0006941), G protein-coupled receptor signaling pathway (GO:0007186), Rho protein signal transduction (GO:0007266), establishment of cell polarity (GO:0030010), actin cytoskeleton organization (GO:0030036), positive regulation of DNA-templated transcription (GO:0045893), regulation of small GTPase mediated signal transduction (GO:0051056)

GO Molecular Function (4): G protein-coupled receptor binding (GO:0001664), guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
RHO GTPase cycle	5
Signal Transduction	2
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Sema4D in semaphorin signaling	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Axon guidance	1
Signaling by GPCR	1
Semaphorin interactions	1
Nervous system development	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
small GTPase-mediated signal transduction	2
GTPase regulator activity	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
muscle contraction	1
G protein-coupled receptor activity	1
signal transduction	1
establishment or maintenance of cell polarity	1
cytoskeleton organization	1
actin filament-based process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of intracellular signal transduction	1
signaling receptor binding	1
GTP binding	1
GDP binding	1
GTPase activity	1
enzyme activator activity	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF11	GNA12	Q03113	987
ARHGEF11	RHOA	P06749	964
ARHGEF11	PLXNB1	O43157	952
ARHGEF11	SLC1A6	P48664	914
ARHGEF11	GNA13	Q14344	897
ARHGEF11	SPTBN2	O15020	890
ARHGEF11	PLXNB2	O15031	885
ARHGEF11	ARRB1	P49407	876
ARHGEF11	RGS21	Q2M5E4	793
ARHGEF11	TJP1	Q07157	790
ARHGEF11	RGS8	P57771	788
ARHGEF11	RGS17	Q9UGC6	785
ARHGEF11	RGS20	O76081	785
ARHGEF11	SEMA4D	Q92854	783
ARHGEF11	RGS5	O15539	779

IntAct

402 interactions, top by confidence:

A	B	Type	Score
RHOA	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.900
ARHGEF11	RHOA	psi-mi:“MI:0407”(direct interaction)	0.900
RHOA	ARHGEF11	psi-mi:“MI:0914”(association)	0.900
RHOA	ARHGEF11	psi-mi:“MI:0915”(physical association)	0.900
ARHGEF12	GIPC1	psi-mi:“MI:0914”(association)	0.720
PLXNB1	ARHGEF11	psi-mi:“MI:0915”(physical association)	0.610
PLXNB1	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.610
ABCA1	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.610
RHOC	ARHGEF11	psi-mi:“MI:0914”(association)	0.530
TRMT61A	ARHGEF11	psi-mi:“MI:0914”(association)	0.530
PAK5	ARHGEF11	psi-mi:“MI:0914”(association)	0.530
ARHGEF11	CDC42	psi-mi:“MI:0407”(direct interaction)	0.440
E6	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF11	E6	psi-mi:“MI:0407”(direct interaction)	0.440
NRXN3	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF11	RPS6KA1	psi-mi:“MI:0407”(direct interaction)	0.440
CACNA1D	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
GNG4	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
WWTR1	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
YAP1	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA7	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
BCR	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
RNF146	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (109): GNA12 (Phenotypic Enhancement), GNA13 (Phenotypic Enhancement), ARHGEF11 (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS), ARAP2 (Co-fractionation), ARHGEF11 (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS), PLXNB3 (Two-hybrid), PLXNB1 (Two-hybrid), ARHGEF11 (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JUG7, A1L390, E9Q0S6, O08774, O14924, O15085, O43182, O54834, O54960, O60307, O75052, P57095, Q13009, Q3U1V8, Q3U214, Q3UHC7, Q4VAC9, Q5DU25, Q5JU85, Q5RBI7, Q5SXA9, Q5VWQ8, Q60610, Q64512, Q6AX33, Q6DN90, Q6NXJ0, Q6P0Q8, Q6P1I6, Q6ZMN7, Q76G19, Q76LL6, Q76M68, Q7T2V3, Q810W7, Q8CGE9, Q8IX03, Q8R0S2, Q8R4H2, Q8WYP3

Diamond homologs: A1IGU3, A1IGU4, A1IGU5, A1ZAY1, E7F1U2, O15068, O15085, O77775, P10569, P15498, P19878, P35991, Q08DN7, Q3LAC4, Q5DU57, Q60992, Q63406, Q69ZK0, Q70Z35, Q80VK6, Q8TCU6, Q96N96, Q9NHV9, Q9NXL2, O60229, P40995, Q1LUA6, Q5BKC9, Q5RDX5, Q64096, Q6RFZ7, Q8CHT1, Q8N5V2, Q9ES67, A0A1D5P556, A0A8C0TYJ0, A4D2P6, A5PKA5, A8MUH7, B7WN72

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GNA12	“up-regulates activity”	ARHGEF11	binding
GNA13	“up-regulates activity”	ARHGEF11	binding
ARHGEF11	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 180 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nephrin family interactions	5	19.3×	8e-04
Downstream signal transduction	6	18.6×	5e-04
EPHB-mediated forward signaling	6	13.0×	8e-04
PCP/CE pathway	5	12.2×	2e-03
RHOV GTPase cycle	5	11.6×	3e-03
RHOU GTPase cycle	5	11.3×	3e-03
FCGR3A-mediated phagocytosis	6	9.1×	2e-03
VEGFA-VEGFR2 Pathway	8	9.1×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	8	16.6×	3e-05
substrate adhesion-dependent cell spreading	6	12.4×	3e-03
endothelial cell migration	5	12.4×	6e-03
B cell receptor signaling pathway	5	12.1×	6e-03
learning	6	10.2×	5e-03
epidermal growth factor receptor signaling pathway	6	9.0×	6e-03
modulation of chemical synaptic transmission	7	7.7×	6e-03
regulation of actin cytoskeleton organization	8	7.6×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	164
Likely benign	11
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
565183	GRCh37/hg19 1q22-23.1(chr1:155636337-158024499)x1	Pathogenic

SpliceAI

5773 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156941366:CCTTA:C	donor_loss	1.0000
1:156941369:TACC:T	donor_loss	1.0000
1:156941370:A:AC	donor_gain	1.0000
1:156941370:ACCT:A	donor_gain	1.0000
1:156941371:C:CC	donor_gain	1.0000
1:156941371:C:CG	donor_loss	1.0000
1:156941371:CCT:C	donor_gain	1.0000
1:156941371:CCTC:C	donor_gain	1.0000
1:156941429:CTACC:C	acceptor_gain	1.0000
1:156941430:TACC:T	acceptor_gain	1.0000
1:156941431:ACC:A	acceptor_gain	1.0000
1:156941432:CC:C	acceptor_gain	1.0000
1:156941432:CCC:C	acceptor_gain	1.0000
1:156941433:CC:C	acceptor_gain	1.0000
1:156941434:C:CC	acceptor_gain	1.0000
1:156941434:C:T	acceptor_gain	1.0000
1:156941434:CTGA:C	acceptor_loss	1.0000
1:156942688:A:AC	donor_gain	1.0000
1:156942689:C:CC	donor_gain	1.0000
1:156942781:C:CC	acceptor_gain	1.0000
1:156943930:GGTAC:G	donor_loss	1.0000
1:156943931:GTACC:G	donor_loss	1.0000
1:156943932:TACC:T	donor_loss	1.0000
1:156943934:CCTGT:C	donor_loss	1.0000
1:156944368:AT:A	donor_gain	1.0000
1:156944434:C:CC	acceptor_gain	1.0000
1:156945015:CTA:C	donor_loss	1.0000
1:156945018:CCT:C	donor_loss	1.0000
1:156945194:CCAC:C	acceptor_gain	1.0000
1:156945195:CAC:C	acceptor_gain	1.0000

AlphaMissense

10160 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156978364:A:G	L117P	1.000
1:156979237:A:G	L108P	1.000
1:156980444:A:C	I89S	1.000
1:156980444:A:G	I89T	1.000
1:156980444:A:T	I89N	1.000
1:156984380:A:T	V61D	1.000
1:156984386:A:G	F59S	1.000
1:156942720:A:G	L1059P	0.999
1:156944385:A:G	W974R	0.999
1:156944385:A:T	W974R	0.999
1:156944390:A:G	L972P	0.999
1:156947844:A:G	W716R	0.999
1:156947844:A:T	W716R	0.999
1:156948399:A:C	S635R	0.999
1:156948399:A:T	S635R	0.999
1:156948401:T:G	S635R	0.999
1:156978364:A:T	L117H	0.999
1:156978370:A:T	V115D	0.999
1:156979234:A:C	I109S	0.999
1:156979234:A:G	I109T	0.999
1:156979234:A:T	I109N	0.999
1:156979279:C:A	G94V	0.999
1:156979281:G:C	N93K	0.999
1:156979281:G:T	N93K	0.999
1:156979285:A:T	V92D	0.999
1:156980447:C:G	R88P	0.999
1:156980477:G:T	A78D	0.999
1:156984389:C:T	G58D	0.999
1:156984391:G:C	F57L	0.999
1:156984391:G:T	F57L	0.999

dbSNP variants (sampled 300 via entrez): RS1000001667 (1:157005862 G>A), RS1000010402 (1:156961315 C>T), RS1000041297 (1:156960884 T>C), RS1000056316 (1:157012660 A>G,T), RS1000089680 (1:157045889 C>G,T), RS1000179255 (1:157043819 T>C), RS1000220807 (1:156999556 A>T), RS1000221077 (1:156973647 T>G), RS1000249435 (1:156954352 C>T), RS1000279781 (1:157026317 T>C), RS1000288230 (1:156973409 A>G), RS1000372992 (1:156987871 T>C), RS1000398621 (1:156980331 G>A,T), RS1000411768 (1:156992890 T>C), RS1000434484 (1:157033079 G>T)

Disease associations

OMIM: gene MIM:605708 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST003989_40	Chin dimples	2.000000e-09
GCST006979_955	Heel bone mineral density	3.000000e-09
GCST008839_496	Height	2.000000e-16
GCST010697_36	Cortical surface area (min-P)	5.000000e-08
GCST010698_82	Subcortical volume (min-P)	4.000000e-20
GCST010699_62	Brain morphology (min-P)	2.000000e-26
GCST010700_48	Cortical thickness (MOSTest)	2.000000e-10
GCST010701_53	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_160	Subcortical volume (MOSTest)	1.000000e-21
GCST010703_149	Brain morphology (MOSTest)	2.000000e-09
GCST90002388_627	Lymphocyte count	8.000000e-12
GCST90002394_84	Monocyte percentage of white cells	4.000000e-12
GCST90002397_775	Mean spheric corpuscular volume	7.000000e-12
GCST90002400_526	Plateletcrit	3.000000e-10
GCST90002402_499	Platelet count	5.000000e-12

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004587	lymphocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0007985	platelet crit
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523642 (PROTEIN COMPLEX)

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression, affects expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
coumarin	increases phosphorylation	1
muconaldehyde	decreases expression	1
fasudil	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Acetaminophen	decreases expression	1
Caffeine	affects phosphorylation	1
Methapyrilene	increases methylation	1
Ozone	affects expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Tacrolimus	increases expression	1
Asbestos, Crocidolite	affects expression	1
Antirheumatic Agents	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4419741	Binding	Inhibition of FLAG-tagged human PDZ RhoGEF DH-PH module expressed in mouse NIH/3T3 cells assessed as reduction in human full length RhoA (1 to 193 residues) interaction with PDZ RhoGEF at 30 to 50 uM incubated for 1 hr by Western blot analy	Small-molecule inhibitors targeting g-protein-coupled rho guanine nucleotide exchange factors

Clinical trials (associated diseases)

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