ARHGEF7

Summary

ARHGEF7 (Rho guanine nucleotide exchange factor 7, HGNC:15607) is a protein-coding gene on chromosome 13q34, encoding Rho guanine nucleotide exchange factor 7 (Q14155). Acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling. It is a selective cancer dependency (DepMap: 34.1% of cell lines).

This gene encodes a protein that belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It forms a complex with the small GTP binding protein Rac1 and recruits Rac1 to membrane ruffles and to focal adhesions. Multiple alternatively spliced transcript variants encoding different isoforms have been observed for this gene.

Source: NCBI Gene 8874 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 117 total
• Phenotypes (HPO): 39
• Cancer dependency (DepMap): dependent in 34.1% of screened cell lines
• MANE Select transcript: NM_001354046

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15607
Approved symbol	ARHGEF7
Name	Rho guanine nucleotide exchange factor 7
Location	13q34
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0142, PIXB, DKFZp761K1021, Nbla10314, DKFZp686C12170, BETA-PIX, COOL1, P85SPR, P85, P85COOL1, P50BP, PAK3, P50
Ensembl gene	ENSG00000102606
Ensembl biotype	protein_coding
OMIM	605477
Entrez	8874

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 17 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000218789, ENST00000317133, ENST00000375723, ENST00000375736, ENST00000375739, ENST00000375741, ENST00000422836, ENST00000426073, ENST00000426768, ENST00000449979, ENST00000466143, ENST00000467053, ENST00000469877, ENST00000478679, ENST00000483189, ENST00000483540, ENST00000491688, ENST00000491775, ENST00000544132, ENST00000646102, ENST00000700426, ENST00000923412

RefSeq mRNA: 27 — MANE Select: NM_001354046 NM_001113511, NM_001113512, NM_001113513, NM_001320851, NM_001320852, NM_001320853, NM_001320854, NM_001330597, NM_001330598, NM_001354046, NM_001354047, NM_001354048, NM_001354049, NM_001354050, NM_001354051, NM_001354052, NM_001354053, NM_001354054, NM_001354055, NM_001354056, NM_001354057, NM_001354058, NM_001354059, NM_001354060, NM_001354061, NM_003899, NM_145735

CCDS: CCDS32009, CCDS45068, CCDS45069, CCDS81781, CCDS86360, CCDS86361, CCDS86362, CCDS91837, CCDS9521

Canonical transcript exons

ENST00000646102 — 22 exons

Exon	Start	End
ENSE00000686825	111283139	111283363
ENSE00000686829	111286147	111286240
ENSE00000686833	111288354	111288443
ENSE00000686841	111300748	111300847
ENSE00000686844	111301478	111301532
ENSE00001468195	111292118	111292294
ENSE00001742777	111280272	111280350
ENSE00003475192	111280538	111280677
ENSE00003489227	111205289	111205373
ENSE00003519925	111233205	111233293
ENSE00003522819	111243872	111243966
ENSE00003548813	111217679	111217880
ENSE00003570381	111277587	111277673
ENSE00003587316	111275532	111275678
ENSE00003589730	111153905	111153991
ENSE00003607952	111274731	111274790
ENSE00003623562	111267548	111267670
ENSE00003636788	111273814	111273952
ENSE00003662042	111209872	111210002
ENSE00003675354	111244199	111244294
ENSE00003815716	111115310	111115691
ENSE00003829641	111302991	111305732

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 96.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.3023 / max 2496.6110, expressed in 1812 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136093	16.0435	1796
136114	4.2693	913
136094	3.2247	1335
136103	2.1967	531
136092	1.8357	409
136095	0.7432	327
136112	0.5157	96
136113	0.4232	190
136090	0.3908	186
136091	0.3517	179

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	96.98	gold quality
sural nerve	UBERON:0015488	96.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.68	gold quality
cerebellar cortex	UBERON:0002129	96.63	gold quality
cerebellar hemisphere	UBERON:0002245	96.62	gold quality
cerebellum	UBERON:0002037	96.21	gold quality
tibial artery	UBERON:0007610	96.14	gold quality
popliteal artery	UBERON:0002250	96.13	gold quality
cortical plate	UBERON:0005343	96.11	gold quality
cerebellar vermis	UBERON:0004720	96.01	gold quality
upper leg skin	UBERON:0004262	95.69	gold quality
skin of hip	UBERON:0001554	95.66	gold quality
right coronary artery	UBERON:0001625	95.62	gold quality
adrenal tissue	UBERON:0018303	95.49	gold quality
aorta	UBERON:0000947	95.43	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.38	gold quality
left coronary artery	UBERON:0001626	95.28	gold quality
skin of abdomen	UBERON:0001416	95.20	gold quality
skin of leg	UBERON:0001511	95.17	gold quality
primary visual cortex	UBERON:0002436	95.12	gold quality
tibial nerve	UBERON:0001323	95.11	gold quality
omental fat pad	UBERON:0010414	95.05	gold quality
right frontal lobe	UBERON:0002810	95.02	gold quality
peritoneum	UBERON:0002358	95.00	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.95	gold quality
descending thoracic aorta	UBERON:0002345	94.90	gold quality
blood vessel layer	UBERON:0004797	94.88	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.83	gold quality
coronary artery	UBERON:0001621	94.71	gold quality
ascending aorta	UBERON:0001496	94.61	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	12.40
E-GEOD-93593	yes	4.06
E-GEOD-110499	no	84.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

119 targeting ARHGEF7, 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-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• bFGF- and NGF-induced phosphorylation of p85 betaPIX mediates Rac1 activation, which in turn regulates cytoskeletal reorganization at growth cones, but not translocation of the PIX complex. (PMID:14557270)
• the interaction of the betaPIX.WASP.SPIN90 complex with Nck is crucial for stable cell adhesion and can be dynamically modulated by SPIN90 phosphorylation that is dependent on cell adhesion and ERK activation (PMID:14559906)
• PIX protein is tightly associated with the GIT family ARF GTPase-activating proteins as a multimeric nexus capable of linking together important signaling molecules. (PMID:15212761)
• PAK1 recruitment to the T cell-antigen-presenting cell interface required interaction with PIX. (PMID:15864311)
• These results suggest that the formation of the complex consisting of Nox1, betaPix, and NoxO1 is likely to be a critical step in EGF-induced ROS generation. (PMID:16329988)
• the SH3 domain of betaPix specifically interacts with a proline-arginine motif (PxxxPR) present within the ubiquitin ligase Cbl and Pak1 kinase. Cdc42/betaPix complex blocks Cbl’s ability to downregulate EGFR. (PMID:16407834)
• Rac1-beta-Pix interaction is required for Rac1 activation by beta-Pix as well as for Rac1-mediated spreading (PMID:16492808)
• These data strongly suggest that, in addition to the known SAP-interacting kinase Fyn, PIX may be another key player in SAP-mediated T cell activation. (PMID:16983070)
• Tiam1 and betaPIX mediate OxPAPC-induced Rac activation, cytoskeletal remodeling, and barrier protective response in pulmonary endothelium (PMID:17219408)
• The association of PLCgamma1 with complexes containing GIT1 and beta-Pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, PLCgamma1 is also involved in the activation of Cdc42 and Rac1. (PMID:17562871)
• PKA-dependent phosphorylation modulates PIXB activity through 14-3-3-beta binding. (PMID:18160719)
• mutant betaPIX lacking guanine nucleotide exchange factor activity inhibited lamellipodium formation (PMID:18325335)
• These results identify p66Shc and FOXO3a as novel partners of beta(1)Pix and represent the first direct evidence of beta(1)Pix in cell proliferation via Erk/p66Shc-dependent and Akt-independent mechanisms. (PMID:18385518)
• Data show that the Rac1 guanine exchange factor- beta-Pix, localizes to focal contacts in human primary Schwannoma cells. (PMID:18445079)
• Beta-PIX regulates nitric oxide synthase type 2 (NOD2) trafficking and NOD2-dependent signal transduction in primary human monocytes and cell line THP-1. (PMID:18684957)
• betaPIX and GIT1 regulate the hepatocyte growth factor-induced and Rac1-dependent membrane transport of WAVE2 and consequently, lamellipodia formation. (PMID:19303398)
• MYO18A is a novel binding partner of the PAK2/betaPIX/GIT1 complex and suggest that MYO18A may play an important role in regulating epithelial cell migration via affecting multiple cell machineries. (PMID:19923322)
• betaPix up-regulates NHE3 membrane expression and activity by Shank2-mediated protein-protein interaction and by activating Rho GTPases in the apical regions of epithelial cells (PMID:20080968)
• Data show that podocalyxin overexpression in human embryonic kidney cells up-regulates Rac1 activity, which depends on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. (PMID:20395446)
• Downstream effects of phosphorylation of ARHGEF7 through LRRK2 could be (i) a feedback control mechanism for LRRK2 activity as well as (ii) an impact of LRRK2 on actin cytoskeleton regulation (PMID:21048939)
• Results describe the role of beta-Pix in the negative regulation of focal adhesion maturation and the promotion of lamellipodial protrusion and focal adhesion turnover to drive cell migration. (PMID:21423176)
• a model by which SNX27 regulates trafficking of beta-Pix to focal adhesions and thereby influences cell motility. (PMID:21926430)
• In vivo migratory capacity of mesenchymal stromal cells depends upon the expression level of beta-PIX. (PMID:22087847)
• It has identified and characterized a novel interaction between CaM and beta-p21-activated kinase interacting exchange factor (beta-PIX), a putative guanine exchange factor implicated in cell signaling. (PMID:22588125)
• Inhibition of glycogen synthase kinase (GSK)-3beta increases the migration capacity of mesenchymal stromal cells during ex vivo expansion. (PMID:23288365)
• Data suggest a coordination between paxillin kinase linker (PKL)/Vav2 signaling and PKL/beta-PIX signaling during cell migration. (PMID:23615439)
• BETA-PIX is a novel downstream signalling mediator during invadopodia formation. (PMID:23740575)
• beta1Pix functions as a transcriptional regulator of beta-catenin signaling through direct interaction with beta-catenin, an action that may be functionally relevant to colon cancer biology. (PMID:24129564)
• Data indicate that suppression of c-Cbl protein by rho guanine nucleotide exchange factor 7 (Cool-1) may be critical for generation of at least a subset of glioblastoma (GBM). (PMID:24458840)
• BetaPix phosphorylation at Ser-340 upregulates Nox1 through Rac activation. (PMID:24792722)
• The interaction of betaPix with srGAP1 is critical for maintaining suppressive crosstalk between Cdc42 and RhoA during 3D collagen migration. (PMID:25150978)
• GIT1/betaPIX/Rac1/PAK pathway plays a crucial role in regulating GABA(A)R synaptic stability and hence inhibitory synaptic transmission with important implications for inhibitory plasticity and information processing in the brain. (PMID:25284783)
• Conversely, increased expression of betaPIX in breast cancer cell lines re-couples the Hippo kinase cassette to Yap/Taz, promoting localization of Yap/Taz to the cytoplasm and inhibiting cell migration and proliferation. (PMID:25425573)
• Phosphorylation of LRRK2 by casein kinase 1alpha regulates trans-Golgi clustering via differential interaction with ARHGEF7. (PMID:25500533)
• Data show the role of Rho guanine nucleotide exchange factor 7 (beta-PIX) to the regulation of high mobility of lung adenocarcinoma cell line H1299 via regulation of focal adhesions dynamics, changes in actin cytoskeleton organization and cell polarity. (PMID:25683605)
• Data show association of G protein-coupled receptor kinase-interacting protein 1 (GIT1), p21-activated kinase interacting exchange factor (betaPIX), and p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1) with centrosomes. (PMID:27012601)
• we discuss recent findings in key physiological systems that exemplify current understanding of the function of this important regulatory complex. Further, we draw attention to gaps in crucial information that remain to be filled to allow a better understanding of the many roles of the GIT-PIX complex in health and disease (PMID:27182061)
• each mutation in LRRK2 and ARHGEF7 demonstrated its unique functional property, which may contribute to the pathogenesis of Parkinson disease (PMID:27423549)
• Traction forces generated by beta-PIX knockdown cells are increased relative to those in control cells, a result consistent with an unexpected enhancement in the migration of single beta-PIX knockdown cells and monolayers of such cells. Authors propose that targeting beta-PIX might be a means of promoting epithelialization of wounds in vivo. (PMID:28596238)
• Data suggest that Scribble PDZ-domain-1 and PDZ-domain-3 are major domains that interact with beta-PIX and exhibit distinct binding hierarchy in interactions between individual Scribble PDZ domains and beta-PIX. (Scribble = scribbled planar cell polarity protein; beta-PIX = Rho guanine nucleotide exchange factor 7) (PMID:29061852)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef7a	ENSDARG00000006299
danio_rerio	arhgef7b	ENSDARG00000073848
mus_musculus	Arhgef7	ENSMUSG00000031511
rattus_norvegicus	Arhgef7	ENSRNOG00000012934

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), PLEKHG1 (ENSG00000120278), MCF2L (ENSG00000126217), ARHGEF6 (ENSG00000129675), ARHGEF9 (ENSG00000131089), VAV3 (ENSG00000134215), VAV1 (ENSG00000141968), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), TIAM1 (ENSG00000156299), KALRN (ENSG00000160145), VAV2 (ENSG00000160293), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), SESTD1 (ENSG00000187231), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 7 — Q14155 (reviewed: Q14155)

Alternative names: Beta-Pix, COOL-1, PAK-interacting exchange factor beta, p85

All UniProt accessions (12): Q14155, A0A2R8YG42, A0A8V8TQ72, B1ALK7, B1ANY6, C9JAD7, C9JDI6, E7ENL8, E7EU80, E7EUY6, E9PDQ5, F6SJA5

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling. Functions in cell migration, attachment and cell spreading. Promotes targeting of RAC1 to focal adhesions. May function as a positive regulator of apoptosis. Downstream of NMDA receptors and CaMKK-CaMK1 signaling cascade, promotes the formation of spines and synapses in hippocampal neurons.

Subunit / interactions. Interacts with PAK kinases through the SH3 domain. Interacts with GIT1 and TGFB1I1. Interacts with PTK2/FAK1 and RAC1. Interacts with ITCH and PARVB. Interacts with unphosphorylated PAK1. Interacts with SCRIB; interaction is direct and may play a role in regulation of apoptosis. Interacts with FRMPD4 (via N-terminus). Interacts with CaMK1. Interacts with BIN2. Interacts with YWHAZ. Interacts (via PH domain) with NOX1 (via FAD-binding FR-type domain). Interacts with SNX27.

Subcellular location. Cell junction. Focal adhesion. Cell projection. Ruffle. Cytoplasm. Cell cortex. Lamellipodium.

Post-translational modifications. Phosphorylated by PTK2/FAK1; this promotes interaction with RAC1. Phosphorylated on Ser-694 by CaMK1; enhancement of GEF activity and downstream activation of RAC1.

Isoforms (6)

UniProt ID	Names	Canonical?
Q14155-4	4	yes
Q14155-1	1
Q14155-2	2
Q14155-3	3
Q14155-5	5
Q14155-6	6

RefSeq proteins (27): NP_001106983, NP_001106984, NP_001106985, NP_001307780, NP_001307781, NP_001307782, NP_001307783, NP_001317526, NP_001317527, NP_001340975, NP_001340976, NP_001340977, NP_001340978, NP_001340979, NP_001340980, NP_001340981, NP_001340982, NP_001340983, NP_001340984, NP_001340985, NP_001340986, NP_001340987, NP_001340988, NP_001340989, NP_001340990, NP_003890, NP_663788 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001452	SH3_domain	Domain
IPR001715	CH_dom	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035789	BetaPIX_SH3	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily
IPR046376	PH_Cool_Pix	Domain

Pfam: PF00169, PF00307, PF00621, PF07653, PF16614, PF16615

UniProt features (69 total): helix 16, modified residue 14, strand 7, sequence conflict 6, turn 6, splice variant 5, domain 4, compositionally biased region 4, region of interest 3, initiator methionine 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5SXP	X-RAY DIFFRACTION	1.65
1BY1	SOLUTION NMR
1ZSG	SOLUTION NMR
2L3G	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14155-F1	66.31	0.31

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 (14): 153, 176, 249, 257, 518, 694, 1, 2, 560, 579, 645, 664, 1, 2

Function

Pathways and Gene Ontology

Reactome pathways

27 pathways

ID	Pathway
R-HSA-182971	EGFR downregulation
R-HSA-193648	NRAGE signals death through JNK
R-HSA-3928664	Ephrin signaling
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013424	RHOV GTPase cycle
R-HSA-9619229	Activation of RAC1 downstream of NMDARs
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-177929	Signaling by EGFR
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-2682334	EPH-Ephrin signaling
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-422475	Axon guidance
R-HSA-73887	Death Receptor Signaling
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
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: 700 (showing top): ATF_B, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, AAGCAAT_MIR137, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_FOCAL_ADHESION_ASSEMBLY, AAGCCAT_MIR135A_MIR135B

GO Biological Process (16): Golgi organization (GO:0007030), signal transduction (GO:0007165), Rho protein signal transduction (GO:0007266), nervous system development (GO:0007399), positive regulation of fibroblast migration (GO:0010763), lamellipodium assembly (GO:0030032), positive regulation of apoptotic process (GO:0043065), ephrin receptor signaling pathway (GO:0048013), focal adhesion assembly (GO:0048041), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), negative regulation of microtubule nucleation (GO:1905833), positive regulation of lamellipodium morphogenesis (GO:2000394), hematopoietic progenitor cell differentiation (GO:0002244), intracellular signal transduction (GO:0035556), positive regulation of GTPase activity (GO:0043547), positive regulation of growth hormone secretion (GO:0060124)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), protein kinase binding (GO:0019901), gamma-tubulin binding (GO:0043015), protein binding (GO:0005515)

GO Cellular Component (16): ruffle (GO:0001726), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), focal adhesion (GO:0005925), cell cortex (GO:0005938), lamellipodium (GO:0030027), protein-containing complex (GO:0032991), neuron projection (GO:0043005), neuronal cell body (GO:0043025), mitotic spindle pole (GO:0097431), postsynapse (GO:0098794), storage vacuole (GO:0000322), plasma membrane (GO:0005886), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
RHO GTPase cycle	7
Signaling by EGFR	1
Cell death signalling via NRAGE, NRIF and NADE	1
EPH-Ephrin signaling	1
GPCR downstream signalling	1
Post NMDA receptor activation events	1
Signaling by Receptor Tyrosine Kinases	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Axon guidance	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
plasma membrane bounded cell projection	3
intracellular anatomical structure	2
cell leading edge	2
cytoplasm	2
cell periphery	2
organelle organization	1
endomembrane system organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
small GTPase-mediated signal transduction	1
system development	1
fibroblast migration	1
regulation of fibroblast migration	1
positive regulation of cell migration	1
lamellipodium organization	1
plasma membrane bounded cell projection assembly	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cell-substrate junction assembly	1
cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
microtubule nucleation	1
regulation of microtubule nucleation	1
negative regulation of microtubule polymerization	1
positive regulation of developmental process	1
lamellipodium morphogenesis	1
positive regulation of lamellipodium organization	1
regulation of lamellipodium morphogenesis	1
hemopoiesis	1
cell differentiation	1
signal transduction	1
GTPase activity	1

Protein interactions and networks

STRING

1568 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF7	GIT1	Q9Y2X7	998
ARHGEF7	CDC42	P21181	986
ARHGEF7	GIT2	Q14161	981
ARHGEF7	SCRIB	Q14160	980
ARHGEF7	PIK3CB	P42338	962
ARHGEF7	PIK3CD	O00329	955
ARHGEF7	RELA	Q04206	953
ARHGEF7	PXN	P49023	937
ARHGEF7	PAK3	O75914	936
ARHGEF7	SRC	P12931	914
ARHGEF7	PIK3CA	P42336	912
ARHGEF7	CBL	P22681	906
ARHGEF7	REL	Q04864	822
ARHGEF7	RABIF	P47224	805
ARHGEF7	AKT1	P31749	802

IntAct

185 interactions, top by confidence:

A	B	Type	Score
PAK1	ARHGEF7	psi-mi:“MI:2364”(proximity)	0.950
ARHGEF7	PAK1	psi-mi:“MI:0915”(physical association)	0.950
PAK1	ARHGEF7	psi-mi:“MI:0915”(physical association)	0.950
ARHGEF7	PAK1	psi-mi:“MI:0914”(association)	0.950
ARHGEF7	PAK1	psi-mi:“MI:0407”(direct interaction)	0.950
PAK1	ARHGEF7	psi-mi:“MI:0407”(direct interaction)	0.950
ARHGEF7	SCRIB	psi-mi:“MI:0915”(physical association)	0.940
SCRIB	ARHGEF7	psi-mi:“MI:0915”(physical association)	0.940
SCRIB	ARHGEF7	psi-mi:“MI:0403”(colocalization)	0.940
SCRIB	ARHGEF7	psi-mi:“MI:0914”(association)	0.940
PAK1	NCK2	psi-mi:“MI:0914”(association)	0.940
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
PAK2	NCK2	psi-mi:“MI:0914”(association)	0.840
SCRIB	ADRA1D	psi-mi:“MI:0914”(association)	0.820

BioGRID (260): ARHGEF7 (Two-hybrid), ARHGEF7 (Two-hybrid), ARHGEF7 (Affinity Capture-MS), ARHGEF7 (Affinity Capture-MS), ARHGEF7 (Two-hybrid), KDM2A (Co-fractionation), ARHGEF7 (Affinity Capture-MS), ARHGEF7 (Affinity Capture-Western), ARHGEF7 (Proximity Label-MS), ARHGEF7 (Affinity Capture-MS), ARHGEF7 (Affinity Capture-MS), ARHGEF7 (Affinity Capture-MS), ARHGEF7 (Affinity Capture-MS), ARHGEF7 (PCA), ARHGEF7 (Reconstituted Complex)

ESM2 similar proteins: A1IGU3, A1IGU4, A1IGU5, A6QP29, B1AVH7, B2RUP2, B5DFA1, D2H0G5, D3ZFJ3, O15068, O55043, P00530, P07332, P14238, P16879, P55194, P98171, Q0GNC1, Q14155, Q15052, Q27J81, Q3U5C8, Q3UMR0, Q58EX7, Q5VV41, Q5XXR3, Q5ZLR6, Q60I26, Q63406, Q64096, Q6PFY1, Q6PGG2, Q70J99, Q7TNH6, Q80TT2, Q80VK6, Q86WN1, Q8C2K1, Q8C6B2, Q8CJ00

Diamond homologs: A0A0G2JV04, A0JNB0, A1A5H8, A1CEK6, A1DFN5, A1Y2K1, A2QW93, A3LXQ8, A4RF61, A5D8S5, A6H7G2, A6QLK6, A7MBI0, D3ZG83, F1RDG9, O13154, O42287, O43125, O55043, O74749, O75791, O89100, P00523, P00525, P00526, P00528, P05480, P06241, P09324, P10936, P12931, P13115, P13116, P13406, P14084, P14085, P15054, P25020, P27446, P27447

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ARHGEF7	down-regulates	CBLC	binding
ARHGEF7	up-regulates	RAC1
ARHGEF7	up-regulates	LRRK2	binding
LRRK2	up-regulates	ARHGEF7	phosphorylation
PRKCG	up-regulates	ARHGEF7	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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
Ephrin signaling	5	35.2×	1e-05
RHOV GTPase cycle	8	28.2×	1e-07
RHOU GTPase cycle	8	27.5×	1e-07
RHO GTPases activate PKNs	6	23.5×	8e-06
RHOQ GTPase cycle	9	20.1×	1e-07
RHOJ GTPase cycle	8	19.8×	5e-07
RHO GTPases Activate WASPs and WAVEs	5	19.6×	1e-04
Translocation of SLC2A4 (GLUT4) to the plasma membrane	8	15.2×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
mitotic spindle organization	5	13.1×	6e-03
microtubule cytoskeleton organization	7	8.2×	5e-03
intracellular protein localization	7	7.0×	7e-03
cell migration	11	6.5×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	6
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

9568 predictions. Top by Δscore:

Variant	Effect	Δscore
13:111115688:GAAA:G	donor_gain	1.0000
13:111115692:G:GG	donor_gain	1.0000
13:111153899:TTGCA:T	acceptor_loss	1.0000
13:111153900:TGCA:T	acceptor_loss	1.0000
13:111153901:GCAGG:G	acceptor_loss	1.0000
13:111153902:CAG:C	acceptor_loss	1.0000
13:111153903:A:T	acceptor_loss	1.0000
13:111153904:G:T	acceptor_loss	1.0000
13:111153989:GAGGT:G	donor_loss	1.0000
13:111153990:AGGTG:A	donor_loss	1.0000
13:111153991:GGTG:G	donor_loss	1.0000
13:111153992:GTG:G	donor_loss	1.0000
13:111153993:T:G	donor_loss	1.0000
13:111209859:AT:A	acceptor_gain	1.0000
13:111209871:GAC:G	acceptor_gain	1.0000
13:111209998:GTTTG:G	donor_gain	1.0000
13:111210001:TGGTA:T	donor_loss	1.0000
13:111210002:GGT:G	donor_loss	1.0000
13:111210003:G:C	donor_loss	1.0000
13:111210003:G:GG	donor_gain	1.0000
13:111210004:T:A	donor_loss	1.0000
13:111217674:TTTAG:T	acceptor_loss	1.0000
13:111217675:TTAG:T	acceptor_loss	1.0000
13:111217676:TA:T	acceptor_loss	1.0000
13:111217677:A:AG	acceptor_gain	1.0000
13:111217677:A:AT	acceptor_loss	1.0000
13:111217677:AG:A	acceptor_gain	1.0000
13:111217678:G:GG	acceptor_gain	1.0000
13:111217678:GG:G	acceptor_gain	1.0000
13:111217678:GGA:G	acceptor_gain	1.0000

AlphaMissense

5655 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:111115549:T:A	V8D	1.000
13:111115554:T:A	W10R	1.000
13:111115554:T:C	W10R	1.000
13:111115558:T:A	L11H	1.000
13:111115558:T:C	L11P	1.000
13:111115569:G:T	G15W	1.000
13:111115618:T:C	L31P	1.000
13:111115630:T:C	L35P	1.000
13:111115638:G:A	G38R	1.000
13:111115638:G:C	G38R	1.000
13:111115638:G:T	G38W	1.000
13:111115639:G:A	G38E	1.000
13:111217719:C:A	A191E	1.000
13:111217724:T:C	F193L	1.000
13:111217726:T:A	F193L	1.000
13:111217726:T:G	F193L	1.000
13:111217730:T:C	F195L	1.000
13:111217731:T:C	F195S	1.000
13:111217732:C:A	F195L	1.000
13:111217732:C:G	F195L	1.000
13:111217748:G:C	D201H	1.000
13:111217755:T:C	L203P	1.000
13:111217779:T:A	I211N	1.000
13:111217785:T:A	V213D	1.000
13:111217808:T:A	W221R	1.000
13:111217808:T:C	W221R	1.000
13:111217810:G:C	W221C	1.000
13:111217810:G:T	W221C	1.000
13:111217811:T:A	W222R	1.000
13:111217811:T:C	W222R	1.000

dbSNP variants (sampled 300 via entrez): RS1000003352 (13:111150784 C>A,T), RS1000028290 (13:111263632 G>A), RS1000030732 (13:111140590 G>C), RS1000037949 (13:111214206 G>A,T), RS1000048268 (13:111252834 A>G), RS1000073880 (13:111269191 G>C,T), RS1000091101 (13:111224104 C>T), RS1000094501 (13:111141131 T>C), RS1000097901 (13:111196050 A>T), RS1000100344 (13:111253118 G>T), RS1000101823 (13:111188273 C>G,T), RS1000112365 (13:111138068 C>A,G,T), RS1000116429 (13:111218342 T>C), RS1000132210 (13:111215249 T>G), RS1000156466 (13:111253500 A>G)

Disease associations

OMIM: gene MIM:605477 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000194	Open mouth
HP:0000215	Thick upper lip vermilion
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000336	Prominent supraorbital ridges
HP:0000340	Sloping forehead
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000490	Deeply set eye
HP:0000582	Upslanted palpebral fissure
HP:0000709	Psychosis
HP:0000711	Restlessness
HP:0000713	Agitation
HP:0000718	Aggressive behavior
HP:0000736	Short attention span
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001212	Prominent fingertip pads
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001348	Brisk reflexes
HP:0001419	X-linked recessive inheritance
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000386_7	Bilirubin levels	8.000000e-06
GCST000401_13	Menopause (age at onset)	3.000000e-08
GCST000880_2	Menarche (age at onset)	6.000000e-08
GCST002248_10	Fasting insulin (dietary factor interaction)	4.000000e-06
GCST002253_12	Homeostasis model assessment of insulin resistance (dietary factor interaction)	2.000000e-06
GCST006976_113	Macular thickness	9.000000e-12
GCST009211_7	Choroid plexus volume	3.000000e-06
GCST009252_2	Skin aging measurement	4.000000e-08
GCST012053_8	Weight	9.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004570	bilirubin measurement
EFO:0004704	age at menopause
EFO:0004703	age at menarche
EFO:0008111	diet measurement
EFO:0004501	HOMA-IR
EFO:0004338	body weight

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment, increases methylation	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
2,2’,4,4’-tetrabromodiphenyl ether	increases expression, decreases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
beta-methylcholine	affects expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	affects binding, increases reaction	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one	decreases expression, increases activity	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E1QU	HAP1 ARHGEF7 (-) 1	Cancer cell line	Male
CVCL_E1QV	HAP1 ARHGEF7 (-) 2	Cancer cell line	Male
CVCL_E1QW	HAP1 ARHGEF7 (-) 3	Cancer cell line	Male
CVCL_E1QX	HAP1 ARHGEF7 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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