ARHGAP4 is a multi-domain Rho GTPase-activating protein that integrates cytoskeletal regulation with the control of cell and axon motility [PMID:12414125, PMID:17804252]. Recombinant ARHGAP4 stimulates the intrinsic GTPase activity of Rac1, Cdc42, and RhoA, establishing it as a functional GAP for multiple Rho-family members PMID:12414125. Its modular architecture partitions these activities: the FCH domain directs localization to the leading edges of migrating cells and to axon growth cones, while the GAP domain and C-terminus are required for its inhibition of cell migration and axon outgrowth PMID:17804252. Through its RhoGAP and SH3 domains, ARHGAP4 assembles a complex with the septins SEPT2 and SEPT9 that reorganizes focal adhesions and modulates integrin-β1–dependent migration and invasion PMID:34524873, and it suppresses epithelial-to-mesenchymal transition and focal-adhesion–driven force generation, with Septin9 acting as a negative regulator that promotes EMT via FAK/Src signaling PMID:32378260. Beyond its canonical GAP role, ARHGAP4 functions as a scaffolding and regulatory protein in cancer: it promotes ubiquitination of HDAC2 to suppress β-catenin activation and tumor cell invasion PMID:30958531, binds p53 to repress DRAM1-dependent apoptosis in acute myeloid leukemia PMID:37443303, and drives colorectal cancer stemness through a MYH9/β-catenin/c-Jun feedback loop PMID:40817404. Its expression is suppressed by miR-939-5p PMID:32021284.
| Year | Confidence | Finding | PMIDs | Journal |
|---|---|---|---|---|
| 2002 | High | Recombinant ARHGAP4 stimulates the GTPase activity of Rac1, Cdc42, and RhoA in vitro, establishing it as a functional GAP for multiple Rho family members. | PMID:12414125 | Brain research. Molecular brain research |
| 2002 | Medium | Endogenous ARHGAP4 localizes to the Golgi complex and can redistribute to microtubules during mitosis; it is also detected at the tips of differentiating neurites in PC12 cells. | PMID:12414125 | Brain research. Molecular brain research |
| 2007 | Medium | The FCH domain of ARHGAP4 is required for localizing the protein to the leading edges of migrating NIH/3T3 cells and to axon growth cones, while the GAP domain and C-terminus are necessary for ARHGAP4-mediated inhibition of cell migration and axon outgrowth. | PMID:17804252 | Molecular and cellular neurosciences |
| 2007 | Medium | Overexpression of ARHGAP4 inhibits NIH/3T3 cell migration and hippocampal axon outgrowth, establishing a functional role as an inhibitor of cell and axon motility. | PMID:17804252 | Molecular and cellular neurosciences |
| 2019 | Medium | ARHGAP4 interacts with and promotes ubiquitination of HDAC2, which in turn inhibits β-catenin activation, suppressing MMP2/MMP9 expression and pancreatic cancer cell invasion and migration. | PMID:30958531 | Carcinogenesis |
| 2019 | Medium | ARHGAP4 overexpression inhibits cell viability, glucose uptake, lactate release, PKM2 expression, and mTOR/HIF-1α pathway activation in pancreatic cancer cells; mTOR inhibitor (rapamycin) or HIF-1α inhibitor (YC-1) rescues the morphological changes induced by ARHGAP4 downregulation, placing ARHGAP4 upstream of the mTOR/HIF-1α axis in the Warburg effect. | PMID:31303760 | OncoTargets and therapy |
| 2020 | Medium | miR-939-5p directly targets and suppresses ARHGAP4 expression (validated by luciferase reporter assay), thereby promoting pancreatic cancer cell viability, invasion, and migration; ARHGAP4 overexpression reverses these effects. | PMID:32021284 | OncoTargets and therapy |
| 2020 | Medium | ARHGAP4 suppresses epithelial-to-mesenchymal transition (EMT) in human mammary epithelial cells, regulating epithelial/mesenchymal marker expression, cell proliferation, migration, 3D morphogenesis, and focal adhesion/stress fiber-driven force generation; Septin9 was identified by proteomics as a negative regulator of ARHGAP4 that promotes EMT via FAK/Src signaling. | PMID:32378260 | FASEB journal |
| 2021 | High | ARHGAP4 forms a complex with SEPT2 and SEPT9 via its RhoGAP domain and SH3 domain; silencing ARHGAP4 or overexpressing SEPT2/SEPT9 independently induces reorganization of focal adhesions with upregulation of Integrin Beta 1, enhancing cell migration and invasion in a microenvironment-dependent manner. | PMID:34524873 | Molecular biology of the cell |
| 2023 | Medium | ARHGAP4 binds p53 to inhibit DRAM1 expression in AML cells; ARHGAP4 knockdown activates DRAM1 signaling and induces apoptosis, while DRAM1 knockdown rescues the defects caused by ARHGAP4 deletion, placing ARHGAP4 upstream of p53/DRAM1 in AML leukemogenesis. | PMID:37443303 | Oncogene |
| 2024 | Low | ARHGAP4 knockdown inhibits migration and invasion of colon cancer cells and decreases expression of TGF-β1, p-Smad2, and p-Smad3, while increasing E-cadherin and decreasing N-cadherin/Vimentin, placing ARHGAP4 upstream of the TGF-β/Smad pathway and EMT in colon cancer. | PMID:38805788 | Biochemical and biophysical research communications |
| 2024 | Low | ARHGAP4 promotes apoptosis and inflammation in ovarian granulosa cells via the PI3K-Akt signaling pathway. | PMID:38355537 | Journal of ovarian research |
| 2025 | Medium | ARHGAP4 drives colorectal cancer stemness through a positive feedback loop with MYH9/β-catenin/c-Jun, as demonstrated by co-immunoprecipitation (ARHGAP4-MYH9 interaction), chromatin immunoprecipitation (c-Jun binding), and FRAP. | PMID:40817404 | NPJ precision oncology |