{"gene":"ARHGAP17","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2000,"finding":"NADRIN (ARHGAP17) contains a GAP domain that activates RhoA, Rac1, and Cdc42 GTPases in vitro. Expression in NIH3T3 cells reduced actin stress fibers and ruffled membranes. In PC12 cells, NADRIN co-localized with synaptotagmin at neurite termini and with cortical actin filaments. Expression of NADRIN or its coiled-coil+GAP domain mutant enhanced Ca2+-dependent exocytosis, while a GAP-domain-lacking mutant inhibited exocytosis, establishing that GAP activity is required for its role in regulated exocytosis.","method":"In vitro GAP assay, NIH3T3 cell morphology, PC12 cell co-localization and exocytosis assay with domain-deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro GAP activity assay plus domain-deletion mutagenesis with functional exocytosis readout in two cell types","pmids":["10967100"],"is_preprint":false},{"year":2002,"finding":"Three novel splice variants of NADRIN (ARHGAP17) were identified (nadrin-102, -104, -116, -126). Nadrin-116 inhibited NGF-dependent neurite outgrowth in a GAP-activity-dependent manner, while other variants had no effect. The 66-kDa C-terminal fragment of nadrin-102 and nadrin-116 localized to the nucleus, and NGF-induced differentiation accelerated this nuclear translocation.","method":"Splice variant identification, PC12 cell neurite outgrowth assay with GAP-mutants, subcellular fractionation and localization","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — isoform-specific functional assays with GAP-activity mutants and localization data, single lab","pmids":["12358749"],"is_preprint":false},{"year":2004,"finding":"The BAR domain of RICH-1 (ARHGAP17) binds membrane lipids and deforms spherical liposomes into striated tubes, consistent with oligomerization via a coiled-coil region within the BAR domain. RICH-1 forms oligomers in the presence of the chemical cross-linker BS3.","method":"Liposome tubulation assay, lipid-binding assay, chemical crosslinking (BS3)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical assays with lipid binding and crosslinking, single lab, two orthogonal methods","pmids":["15240152"],"is_preprint":false},{"year":2006,"finding":"RICH1 (ARHGAP17) binds the scaffolding protein angiomotin (Amot), which targets RICH1 to a tight junction complex containing Pals1, Patj, and Par-3. Regulation of Cdc42 by RICH1 is necessary for maintenance of tight junctions in MDCK epithelial cells. The coiled-coil domain of Amot, required for Rich1 binding, is also necessary for Amot localization to apical membranes and for Amot to relocalize Pals1 and Par-3 to internal puncta.","method":"Proteomic screen (functional and protein interaction), Co-IP, MDCK cell tight junction assays, domain-deletion experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic screen confirmed by Co-IP, domain-mapping, and functional TJ-maintenance assay in epithelial cells","pmids":["16678097"],"is_preprint":false},{"year":2012,"finding":"Nadrin (ARHGAP17) is present in platelets where it co-localizes with actin-rich regions and Rho GTPases. Different Nadrin isoforms selectively regulate RhoA, Cdc42, or Rac1. The BAR domain controls Nadrin-GAP activity and directs the GAP to the plasma membrane. Nadrin overexpression strongly reduced platelet cell adhesion on fibrinogen and controls RhoA-mediated stress fiber and focal adhesion formation.","method":"Isoform-specific overexpression, Rho GTPase activity assays, co-localization, spreading/adhesion assay on fibrinogen, BAR domain deletion","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple isoform-specific functional assays with GTPase activity readouts, single lab","pmids":["22975681"],"is_preprint":false},{"year":2013,"finding":"NADRIN (ARHGAP17) expression increased in stellate astrocytes. Induced expression accelerated morphological differentiation of cultured astrocytes into stellate cells in a GAP-activity-dependent manner. NADRIN formed a dimer via amino- and carboxy-terminal domain interaction, which was disrupted by inductive signals (dibutyryl-cAMP, EGF). Upon inductive signals, NADRIN formed a complex with ERM proteins via ERM-binding phosphoprotein 50 (EBP50) through its C-terminal PDZ-binding motif, where it inactivates RhoA.","method":"Immunoprecipitation (co-IP), GAP-activity mutant rescue, astrocyte stellation assay, domain-deletion analysis","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP with domain mapping and GAP-mutant functional assay, single lab","pmids":["23355722"],"is_preprint":false},{"year":2014,"finding":"Nadrin (ARHGAP17) becomes tyrosine-phosphorylated upon platelet activation by Src family kinases (Src, Lyn, Fyn). Phosphorylation leads to isoform- and target-specific regulation: Src-phosphorylation of Nadrin5 mediates Cdc42 inactivation, while Src-phosphorylation of Nadrin2 leads to RhoA and Rac1 activation.","method":"Platelet activation assay, kinase co-IP, phosphorylation assays with Src-family inhibitors, isoform-specific Rho GTPase activity assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — kinase identification with GTPase-activity readout, isoform-specific analysis, single lab","pmids":["24703939"],"is_preprint":false},{"year":2015,"finding":"PKA and PKG phosphorylate ARHGAP17 at serine 702 in platelets, which is mapped using Phos-tag gels. ARHGAP17 binds CIP4 in platelets and Ser-702 phosphorylation interferes with CIP4 binding; reduced CIP4 binding results in enhanced inhibition of cell migration by ARHGAP17. PKA/PKG activation reduces Rac1-GTP levels, and ARHGAP17 is identified as a Rac1-specific GAP mediating this effect.","method":"Phos-tag gel phosphorylation mapping, Co-IP/pulldown of ARHGAP17-CIP4 complex, Rac1-GTP assay (pull-down), cell migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct phosphorylation site mapping by Phos-tag plus functional Co-IP and cell migration assay, multiple orthogonal methods","pmids":["26507661"],"is_preprint":false},{"year":2015,"finding":"Rich1 (ARHGAP17) overexpression in hepatocyte HL7702 epithelial cells causes S-phase arrest, proliferation inhibition, and adhesion decline with decreased F-actin. Rich1 stimulates GTP hydrolysis on both CDC42 and RAC1, attenuating their activity and the phosphorylation of PAK1 and ERK1/2. GAP-domain-deleted Rich1 or Rich1 silencing abolished all these effects, establishing a CDC42/RAC1-PAK1-ERK1/2 signaling axis.","method":"Overexpression/knockdown, Rho GTPase activity assay (GTP hydrolysis), phosphorylation (Western blot), cell cycle analysis, adhesion assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — GAP-domain deletion mutant plus GTPase activity and signaling phosphorylation readouts, single lab","pmids":["26004135"],"is_preprint":false},{"year":2016,"finding":"Arhgap17-deficient mice show increased paracellular permeability and aberrant localization of the apical junction complex in intestinal luminal epithelium, establishing a role for Arhgap17 in regulating transcellular transport and maintaining intestinal barrier integrity in vivo.","method":"Knockout mouse model, paracellular permeability assay, immunofluorescence localization of apical junction complex","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout model with specific epithelial barrier and junction localization readouts, multiple assays","pmids":["27229483"],"is_preprint":false},{"year":2018,"finding":"VEGF long isoform acting through NRP1 controls filopodia formation and cell migration of breast cancer cells by modulating Cdc42 activity via ARHGAP17. Genome-wide expression profiling identified ARHGAP17 as a target gene downstream of the VEGF/NRP1 signal, and VEGF knockout or soluble NRP1 overexpression impaired cell migration concordantly with altered ARHGAP17 expression and Cdc42 activity.","method":"VEGF knockout, soluble NRP1 overexpression, genome-wide expression profiling, Cdc42 activity assay, filopodia imaging","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic loss-of-function with Cdc42 activity assay and filopodia imaging, single lab","pmids":["29971782"],"is_preprint":false},{"year":2018,"finding":"ARHGAP17 overexpression in colon cancer cells inhibits cell growth and invasion and restricts lung metastasis in vivo. Mechanistically, ARHGAP17 increases phosphorylation of GSK3β and decreases β-catenin nuclear localization and transcriptional activity. WIF-1-mediated inhibition of Wnt signaling attenuated the proliferation/invasion promotion caused by ARHGAP17 knockdown, placing ARHGAP17 upstream of Wnt/β-catenin.","method":"Overexpression/knockdown, in vivo metastasis model, Western blot for β-catenin/GSK3β phosphorylation, GSEA, Wnt inhibitor epistasis","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis with WIF-1 plus in vivo model and signaling phosphorylation data, single lab","pmids":["29730655"],"is_preprint":false},{"year":2020,"finding":"ARHGAP17 overexpression abolished pathological cyclic strain-induced apoptosis in human periodontal ligament fibroblasts by inactivating Rac1/Cdc42. Rac1 inhibitors (NSC23766, EHT 1864) attenuated ARHGAP17 knockdown-mediated apoptosis, confirming epistatic placement of ARHGAP17 upstream of Rac1/Cdc42 in the apoptosis pathway.","method":"Cyclic strain model, overexpression/knockdown, Rac1/Cdc42 activity assay, pharmacological inhibition epistasis, apoptosis assay","journal":"Clinical and experimental pharmacology & physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pharmacological epistasis plus GTPase activity assay, single lab","pmids":["32391922"],"is_preprint":false},{"year":2022,"finding":"ARHGAP17 is a Cdc42-specific RhoGAP that localizes to the invadopodia ring during assembly, restricting Cdc42 activity to the invadopodia core. During disassembly, ARHGAP17 translocates from the ring to the core in a process mediated by its interaction with the Cdc42 effector CIP4. Once at the core, ARHGAP17 inactivates Cdc42 to promote invadopodia disassembly, defining a spatiotemporal regulatory mechanism for Cdc42 at invadopodia.","method":"Live imaging, FRAP/localization at invadopodia, Cdc42 activity biosensor (FRET-based), knockdown, Co-IP with CIP4","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — live imaging of spatiotemporal localization combined with Cdc42 activity biosensor, Co-IP with CIP4, and functional KD assays","pmids":["36571786"],"is_preprint":false},{"year":2022,"finding":"RICH1 (ARHGAP17) activates the Hippo kinase cascade in breast cancer cells by competing with Merlin for binding to Amot-p80. This competition is mediated by the BAR domain of RICH1; deletion of the BAR domain abolished RICH1's ability to displace Amot-p80 from Merlin. Loss of RICH1 promoted stemness and disrupted epithelial architecture.","method":"Co-IP (RICH1-Amot-p80-Merlin complex), BAR domain deletion mutant, Hippo pathway kinase activity (MST1/2, LATS), stemness assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain-deletion mutant and functional Hippo-kinase readout, single lab","pmids":["35064101"],"is_preprint":false},{"year":2022,"finding":"ARHGAP17 knockdown in colon cancer cells led to elevated active Rac1 levels, while ARHGAP17 overexpression reduced active Rac1 and sensitized 5-FU-resistant cells to apoptosis. Rac1 inhibitor abolished the anti-apoptotic effect of ARHGAP17 knockdown, and Rac1 overexpression reversed the pro-apoptotic effect of ARHGAP17 overexpression, placing ARHGAP17 upstream of Rac1 in the apoptosis pathway.","method":"Rac1-GTP pull-down assay, overexpression/knockdown, pharmacological Rac1 inhibition epistasis, apoptosis (cleaved caspase-3, PARP), in vivo xenograft","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — GTPase activity assay plus pharmacological epistasis with in vivo confirmation, single lab","pmids":["35293764"],"is_preprint":false},{"year":2023,"finding":"Wdr4, a substrate adaptor of the CUL4 E3 ligase complex, induces ubiquitination and degradation of Arhgap17 in cerebellar granule neuron progenitors (GNPs), thereby activating Rac1 and facilitating cell cycle progression. Loss of Wdr4 in GNPs increased Arhgap17 levels, reduced Rac1 activity, and caused proliferation defects and cerebellar developmental abnormalities.","method":"Genetic mouse KO, ubiquitination assay, Rac1-GTP pull-down, cell cycle analysis, cerebellar immunohistology","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay combined with Rac1 activity assay and in vivo KO phenotype, multiple orthogonal methods","pmids":["36681682"],"is_preprint":false},{"year":2025,"finding":"RICH1 (ARHGAP17) facilitates ubiquitination-mediated degradation of RhoA by binding TRIM21 E3 ligase and enhancing TRIM21-RhoA interaction in breast cancer cells. This leads to decreased STAT3 phosphorylation, increased IFN-γ production/secretion, and promotion of M1-like macrophage polarization.","method":"Co-IP (RICH1-TRIM21-RhoA complex), ubiquitination assay, STAT3 phosphorylation Western blot, cytokine secretion assay, macrophage polarization assay","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP complex identification with ubiquitination assay and downstream signaling readout, single lab","pmids":["41436617"],"is_preprint":false},{"year":2026,"finding":"NME1, whose histidine phosphorylation is required for its activity, modulates CDC42 activity via ARHGAP17, thereby influencing cytoskeletal organization and Hippo pathway activation. Loss of NME1 reduced YAP phosphorylation and promoted YAP nuclear localization, consistent with suppression of Hippo signaling through the NME1-ARHGAP17-CDC42-cytoskeleton axis. Identified using PhastID-based proximity labeling.","method":"PhastID proximity labeling, CDC42 activity assay, YAP phosphorylation/localization assay, loss-of-function","journal":"Life medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — proximity labeling combined with GTPase activity and Hippo pathway readout, single lab, single study","pmids":["41978798"],"is_preprint":false}],"current_model":"ARHGAP17 (also known as RICH1/NADRIN) is a BAR-domain-containing RhoGAP that inactivates Cdc42, Rac1, and RhoA in a context- and isoform-dependent manner; it is regulated by PKA/PKG phosphorylation at Ser-702 (disrupting CIP4 binding), by Src-family-mediated tyrosine phosphorylation (isoform-specific GTPase targeting), and by CUL4-Wdr4-mediated ubiquitination/degradation; it maintains epithelial tight junction integrity via an Amot scaffold complex, controls invadopodia turnover by spatiotemporally restricting Cdc42 activity in a CIP4-dependent manner, activates Hippo signaling by competing with Merlin for Amot-p80 binding, and connects upstream NME1 histidine-phosphorylation to the CDC42-cytoskeleton-Hippo axis."},"narrative":{"mechanistic_narrative":"ARHGAP17 (RICH1/NADRIN) is a BAR-domain–containing RhoGAP that inactivates the Rho-family GTPases Cdc42, Rac1, and RhoA to control actin cytoskeletal remodeling, epithelial junction integrity, and downstream proliferative and morphogenetic signaling [PMID:10967100, PMID:26004135]. Its N-terminal BAR domain binds and tubulates membrane lipids, directing GAP activity to the plasma membrane and supporting oligomerization [PMID:15240152, PMID:22975681], and its GAP activity is required for its cellular effects on actin organization, neurite outgrowth, astrocyte stellation, and exocytosis [PMID:10967100, PMID:15240152, PMID:23355722]. At epithelial tight junctions ARHGAP17 is recruited by the scaffold angiomotin (Amot) into a Pals1/Patj/Par-3 complex where it locally regulates Cdc42 to maintain junction integrity, a role confirmed in vivo by intestinal barrier defects in knockout mice [PMID:16678097, PMID:27229483]. At invadopodia it is spatiotemporally repositioned from the ring to the core via its Cdc42 effector partner CIP4, restricting Cdc42 activity to drive structure disassembly [PMID:36571786]. Through its BAR domain it competes with Merlin for Amot-p80 binding to activate the Hippo kinase cascade and restrain stemness [PMID:35064101], and it links the NME1–CDC42–cytoskeleton axis to Hippo/YAP regulation [PMID:41978798]. ARHGAP17 activity is tuned by PKA/PKG phosphorylation at Ser-702, which disrupts CIP4 binding [PMID:26507661], by Src-family tyrosine phosphorylation that switches its isoform-specific GTPase targeting [PMID:24703939], and by CUL4-Wdr4–mediated ubiquitination and degradation [PMID:36681682]; it also scaffolds TRIM21-dependent ubiquitination of RhoA [PMID:41436617]. Across cancer models ARHGAP17 acts as a growth- and invasion-suppressing GAP upstream of Rac1/Cdc42-PAK1-ERK and Wnt/β-catenin signaling [PMID:26004135, PMID:29730655, PMID:35293764].","teleology":[{"year":2000,"claim":"Established that ARHGAP17/NADRIN is a functional RhoGAP whose catalytic activity drives actin remodeling and regulated exocytosis, defining its core molecular identity.","evidence":"In vitro GAP assay against RhoA/Rac1/Cdc42 plus domain-deletion mutants in NIH3T3 and PC12 cells with exocytosis readout","pmids":["10967100"],"confidence":"High","gaps":["GTPase target specificity in vivo not resolved","structural basis of GAP activity not defined"]},{"year":2002,"claim":"Showed that alternative splicing produces functionally distinct isoforms with isoform-specific effects on neurite outgrowth and nuclear translocation of a C-terminal fragment, indicating isoform-encoded functional diversity.","evidence":"Splice variant identification with GAP-mutant neurite outgrowth assays and subcellular fractionation in PC12 cells","pmids":["12358749"],"confidence":"Medium","gaps":["function of the nuclear C-terminal fragment unknown","single-lab isoform characterization"]},{"year":2004,"claim":"Demonstrated that the BAR domain binds and deforms membranes and mediates oligomerization, providing the structural basis for membrane targeting of the GAP.","evidence":"Liposome tubulation, lipid-binding, and BS3 crosslinking assays in vitro","pmids":["15240152"],"confidence":"Medium","gaps":["lipid species preference not mapped","in-cell consequences of tubulation untested"]},{"year":2006,"claim":"Identified the Amot scaffold as the recruiter of ARHGAP17 to a tight junction complex, explaining how Cdc42 regulation is spatially restricted to maintain epithelial junctions.","evidence":"Proteomic screen, Co-IP, domain mapping, and tight junction maintenance assays in MDCK cells","pmids":["16678097"],"confidence":"High","gaps":["mechanism of GAP activation within the complex unknown","direct vs indirect Amot binding not fully resolved"]},{"year":2012,"claim":"Established that distinct isoforms selectively target RhoA, Cdc42, or Rac1 and that the BAR domain controls both membrane localization and GAP activity in platelets, linking isoform identity to GTPase choice.","evidence":"Isoform-specific overexpression, GTPase activity assays, BAR deletion, and fibrinogen adhesion assays in platelets","pmids":["22975681"],"confidence":"Medium","gaps":["determinants of isoform-specific GTPase selectivity unclear","single-lab characterization"]},{"year":2013,"claim":"Showed that signal-induced conformational change releases an autoinhibitory dimer and routes ARHGAP17 to ERM/EBP50 complexes to inactivate RhoA during astrocyte stellation, revealing a regulated activation switch.","evidence":"Co-IP, domain-deletion analysis, GAP-mutant rescue, and stellation assays in cultured astrocytes","pmids":["23355722"],"confidence":"Medium","gaps":["structural basis of intramolecular dimer not defined","signal-to-conformation coupling not mechanistically resolved"]},{"year":2015,"claim":"Defined PKA/PKG phosphorylation at Ser-702 as a regulatory switch that disrupts CIP4 binding and enhances Rac1-specific inhibition of migration, connecting cyclic-nucleotide signaling to GAP function.","evidence":"Phos-tag site mapping, ARHGAP17-CIP4 Co-IP, Rac1-GTP pulldown, and migration assays in platelets","pmids":["26507661"],"confidence":"High","gaps":["how CIP4 binding gates GAP activity not fully mechanistic","Ser-702 role outside platelets untested"]},{"year":2015,"claim":"Placed ARHGAP17 upstream of a CDC42/RAC1-PAK1-ERK1/2 axis controlling proliferation and adhesion, linking its GAP activity to mitogenic signaling output.","evidence":"Overexpression/knockdown, GTPase activity assays, phospho-Western, and cell cycle/adhesion assays in HL7702 hepatocytes","pmids":["26004135"],"confidence":"Medium","gaps":["direct vs indirect effect on PAK1/ERK not separated","single cell line"]},{"year":2014,"claim":"Revealed that Src-family tyrosine phosphorylation switches isoform-specific GTPase targeting, adding a kinase-controlled layer to ARHGAP17 output during platelet activation.","evidence":"Platelet activation, kinase Co-IP, Src-family inhibitor phosphorylation assays, and isoform-specific GTPase activity assays","pmids":["24703939"],"confidence":"Medium","gaps":["phosphosite identities not mapped","mechanism converting RhoGAP to GTPase-activating output unclear"]},{"year":2016,"claim":"Provided in vivo proof that ARHGAP17 maintains intestinal epithelial barrier integrity through proper apical junction localization, validating the cell-based tight junction model.","evidence":"Arhgap17 knockout mouse with paracellular permeability and junction immunofluorescence","pmids":["27229483"],"confidence":"High","gaps":["GTPase responsible for the in vivo phenotype not pinned down","tissue-specific contribution not dissected"]},{"year":2018,"claim":"Positioned ARHGAP17 as a tumor-suppressing GAP downstream of VEGF/NRP1 and upstream of Wnt/β-catenin, connecting its Cdc42/Rac1 control to cancer cell migration and metastasis.","evidence":"VEGF KO/soluble NRP1, expression profiling, Cdc42 activity and filopodia imaging; plus overexpression/knockdown, in vivo metastasis, and WIF-1 epistasis in colon cancer","pmids":["29971782","29730655"],"confidence":"Medium","gaps":["mechanistic link from GAP activity to β-catenin/GSK3β not direct","single-lab models"]},{"year":2022,"claim":"Established spatiotemporal control of Cdc42 at invadopodia, showing CIP4-mediated ring-to-core translocation of ARHGAP17 drives structure disassembly, a high-resolution mechanistic picture of its GAP function.","evidence":"Live imaging, Cdc42 FRET biosensor, knockdown, and CIP4 Co-IP at invadopodia","pmids":["36571786"],"confidence":"High","gaps":["upstream signal triggering translocation unknown","general applicability beyond invadopodia untested"]},{"year":2022,"claim":"Defined a BAR-domain-dependent competition with Merlin for Amot-p80 that activates the Hippo cascade and restrains stemness, linking ARHGAP17 to Hippo regulation in addition to GTPase control.","evidence":"Co-IP of RICH1-Amot-p80-Merlin, BAR deletion, MST/LATS activity, and stemness assays in breast cancer cells","pmids":["35064101"],"confidence":"Medium","gaps":["whether Hippo effect is GAP-independent not fully resolved","single-lab study"]},{"year":2022,"claim":"Confirmed ARHGAP17 acts upstream of Rac1 to control apoptosis and chemoresistance, reinforcing its GAP-dependent role in cancer cell survival across stress contexts.","evidence":"Rac1-GTP pulldown, pharmacological epistasis, apoptosis markers, and xenograft in colon cancer; cyclic-strain apoptosis model in periodontal fibroblasts","pmids":["35293764","32391922"],"confidence":"Medium","gaps":["downstream apoptotic effectors of Rac1 not specified","single-lab models"]},{"year":2023,"claim":"Identified CUL4-Wdr4–mediated ubiquitination and degradation as a mechanism controlling ARHGAP17 abundance, thereby gating Rac1 activity and neural progenitor proliferation in vivo.","evidence":"Wdr4 mouse KO, ubiquitination assay, Rac1-GTP pulldown, and cerebellar histology","pmids":["36681682"],"confidence":"High","gaps":["ubiquitination sites on ARHGAP17 not mapped","signals regulating Wdr4-ARHGAP17 axis unknown"]},{"year":2025,"claim":"Showed ARHGAP17 scaffolds TRIM21-dependent ubiquitination of RhoA, coupling GTPase degradation to STAT3 suppression and M1 macrophage polarization, extending its function into immune regulation.","evidence":"Co-IP of RICH1-TRIM21-RhoA, ubiquitination assay, STAT3 phospho-Western, cytokine and macrophage polarization assays in breast cancer","pmids":["41436617"],"confidence":"Medium","gaps":["whether scaffolding is GAP-activity-dependent unclear","single-lab study"]},{"year":2026,"claim":"Connected NME1 histidine-phosphorylation to ARHGAP17-CDC42 control of the cytoskeleton and Hippo/YAP signaling, placing ARHGAP17 within an upstream metabolic-kinase input.","evidence":"PhastID proximity labeling, CDC42 activity assay, and YAP phosphorylation/localization with NME1 loss-of-function","pmids":["41978798"],"confidence":"Medium","gaps":["direct NME1-ARHGAP17 interaction vs proximity not distinguished","single study"]},{"year":null,"claim":"How isoform identity, post-translational modification, scaffold binding, and degradation are integrated to determine which GTPase ARHGAP17 acts on in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unified structural model of GTPase selectivity","interplay of Ser-702, Tyr phosphorylation, and ubiquitination not co-analyzed","in vivo isoform-specific functions largely untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,8,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,14,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8,14]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,15]}],"complexes":["Amot tight junction complex (Pals1/Patj/Par-3)"],"partners":["AMOT","CIP4","TRIM21","EBP50","NME1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q68EM7","full_name":"Rho GTPase-activating protein 17","aliases":["Rho-type GTPase-activating protein 17","RhoGAP interacting with CIP4 homologs protein 1","RICH-1"],"length_aa":881,"mass_kda":95.4,"function":"Rho GTPase-activating protein involved in the maintenance of tight junction by regulating the activity of CDC42, thereby playing a central role in apical polarity of epithelial cells. Specifically acts as a GTPase activator for the CDC42 GTPase by converting it to an inactive GDP-bound state. The complex formed with AMOT acts by regulating the uptake of polarity proteins at tight junctions, possibly by deciding whether tight junction transmembrane proteins are recycled back to the plasma membrane or sent elsewhere. Participates in the Ca(2+)-dependent regulation of exocytosis, possibly by catalyzing GTPase activity of Rho family proteins and by inducing the reorganization of the cortical actin filaments. Acts as a GTPase activator in vitro for RAC1","subcellular_location":"Membrane; Cytoplasm; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/Q68EM7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARHGAP17","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000140750","cell_line_id":"CID000592","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"membrane","grade":3}],"interactors":[{"gene":"SH3BP1","stoichiometry":0.2},{"gene":"ARHGAP44","stoichiometry":0.2},{"gene":"VCL","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"EIF3K","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000592","total_profiled":1310},"omim":[{"mim_id":"617716","title":"RHO GTPase-ACTIVATING PROTEIN 44; ARHGAP44","url":"https://www.omim.org/entry/617716"},{"mim_id":"608293","title":"RHO GTPase-ACTIVATING PROTEIN 17; ARHGAP17","url":"https://www.omim.org/entry/608293"},{"mim_id":"300410","title":"ANGIOMOTIN; AMOT","url":"https://www.omim.org/entry/300410"},{"mim_id":"116952","title":"CELL DIVISION CYCLE 42; CDC42","url":"https://www.omim.org/entry/116952"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARHGAP17"},"hgnc":{"alias_symbol":["RICH1","FLJ10308","NADRIN","FLJ13219","WBP15"],"prev_symbol":[]},"alphafold":{"accession":"Q68EM7","domains":[{"cath_id":"1.20.1270.60","chopping":"23-162_173-245","consensus_level":"high","plddt":92.7667,"start":23,"end":245},{"cath_id":"1.10.555.10","chopping":"255-442","consensus_level":"high","plddt":90.2859,"start":255,"end":442}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68EM7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q68EM7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q68EM7-F1-predicted_aligned_error_v6.png","plddt_mean":64.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARHGAP17","jax_strain_url":"https://www.jax.org/strain/search?query=ARHGAP17"},"sequence":{"accession":"Q68EM7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q68EM7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q68EM7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68EM7"}},"corpus_meta":[{"pmid":"16678097","id":"PMC_16678097","title":"A Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16678097","citation_count":303,"is_preprint":false},{"pmid":"10967100","id":"PMC_10967100","title":"Nadrin, a novel neuron-specific GTPase-activating protein involved in regulated exocytosis.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10967100","citation_count":56,"is_preprint":false},{"pmid":"15240152","id":"PMC_15240152","title":"RICH-1 has a BIN/Amphiphysin/Rvsp domain responsible for binding to membrane lipids and tubulation of liposomes.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15240152","citation_count":40,"is_preprint":false},{"pmid":"26507661","id":"PMC_26507661","title":"Cyclic Nucleotide-dependent Protein Kinases Target ARHGAP17 and ARHGEF6 Complexes in Platelets.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26507661","citation_count":28,"is_preprint":false},{"pmid":"30641218","id":"PMC_30641218","title":"ARHGAP17 suppresses tumor progression and up-regulates P21 and P27 expression via inhibiting PI3K/AKT signaling pathway in cervical cancer.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30641218","citation_count":28,"is_preprint":false},{"pmid":"29971782","id":"PMC_29971782","title":"Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29971782","citation_count":25,"is_preprint":false},{"pmid":"27229483","id":"PMC_27229483","title":"Arhgap17, a RhoGTPase activating protein, regulates mucosal and epithelial barrier function in the mouse colon.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27229483","citation_count":23,"is_preprint":false},{"pmid":"22975681","id":"PMC_22975681","title":"Isoform-specific roles of the GTPase activating protein Nadrin in cytoskeletal reorganization of platelets.","date":"2012","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/22975681","citation_count":21,"is_preprint":false},{"pmid":"12358749","id":"PMC_12358749","title":"Identification and functional characterization of nadrin variants, a novel family of GTPase activating protein for rho GTPases.","date":"2002","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12358749","citation_count":21,"is_preprint":false},{"pmid":"26004135","id":"PMC_26004135","title":"Rich1 negatively regulates the epithelial cell cycle, proliferation and adhesion by CDC42/RAC1-PAK1-Erk1/2 pathway.","date":"2015","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/26004135","citation_count":19,"is_preprint":false},{"pmid":"29730655","id":"PMC_29730655","title":"Tumor Suppressive Role of ARHGAP17 in Colon Cancer Through Wnt/β-Catenin Signaling.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29730655","citation_count":17,"is_preprint":false},{"pmid":"35064101","id":"PMC_35064101","title":"RICH1 inhibits breast cancer stem cell traits through activating kinases cascade of Hippo signaling by competing with Merlin for binding to Amot-p80.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35064101","citation_count":16,"is_preprint":false},{"pmid":"32391922","id":"PMC_32391922","title":"ARHGAP17 inhibits pathological cyclic strain-induced apoptosis in human periodontal ligament fibroblasts via Rac1/Cdc42.","date":"2020","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32391922","citation_count":11,"is_preprint":false},{"pmid":"36571786","id":"PMC_36571786","title":"ARHGAP17 regulates the spatiotemporal activity of Cdc42 at invadopodia.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36571786","citation_count":11,"is_preprint":false},{"pmid":"23355722","id":"PMC_23355722","title":"The role of NADRIN, a Rho GTPase-activating protein, in the morphological differentiation of astrocytes.","date":"2013","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23355722","citation_count":11,"is_preprint":false},{"pmid":"24703939","id":"PMC_24703939","title":"Nadrin GAP activity is isoform- and target-specific regulated by tyrosine phosphorylation.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/24703939","citation_count":10,"is_preprint":false},{"pmid":"36681682","id":"PMC_36681682","title":"Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36681682","citation_count":10,"is_preprint":false},{"pmid":"35293764","id":"PMC_35293764","title":"ARHGAP17 enhances 5-Fluorouracil-induced apoptosis in colon cancer cells by suppressing Rac1.","date":"2022","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/35293764","citation_count":3,"is_preprint":false},{"pmid":"38724713","id":"PMC_38724713","title":"ARHGAP17 Inhibits Hepatocellular Carcinoma Progression by Inactivation of Wnt/β-Catenin Signaling Pathway.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38724713","citation_count":1,"is_preprint":false},{"pmid":"38456539","id":"PMC_38456539","title":"RICH1 is a novel key suppressor of isoproterenol‑ or angiotensin II‑induced cardiomyocyte hypertrophy.","date":"2024","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/38456539","citation_count":0,"is_preprint":false},{"pmid":"41436617","id":"PMC_41436617","title":"RICH1 enhances pro-inflammatory TAM infiltration in breast cancer via promoting TRIM21-mediated ubiquitination of RhoA and inhibiting STAT3 phosphorylation.","date":"2025","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41436617","citation_count":0,"is_preprint":false},{"pmid":"41978798","id":"PMC_41978798","title":"Histidine phosphorylation of NME1 regulates the Hippo pathway via the ARHGAP17-CDC42-cytoskeleton axis.","date":"2026","source":"Life medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41978798","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12926,"output_tokens":5339,"usd":0.059431,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13622,"output_tokens":5248,"usd":0.099655,"stage2_stop_reason":"end_turn"},"total_usd":0.159086,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"NADRIN (ARHGAP17) contains a GAP domain that activates RhoA, Rac1, and Cdc42 GTPases in vitro. Expression in NIH3T3 cells reduced actin stress fibers and ruffled membranes. In PC12 cells, NADRIN co-localized with synaptotagmin at neurite termini and with cortical actin filaments. Expression of NADRIN or its coiled-coil+GAP domain mutant enhanced Ca2+-dependent exocytosis, while a GAP-domain-lacking mutant inhibited exocytosis, establishing that GAP activity is required for its role in regulated exocytosis.\",\n      \"method\": \"In vitro GAP assay, NIH3T3 cell morphology, PC12 cell co-localization and exocytosis assay with domain-deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro GAP activity assay plus domain-deletion mutagenesis with functional exocytosis readout in two cell types\",\n      \"pmids\": [\"10967100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Three novel splice variants of NADRIN (ARHGAP17) were identified (nadrin-102, -104, -116, -126). Nadrin-116 inhibited NGF-dependent neurite outgrowth in a GAP-activity-dependent manner, while other variants had no effect. The 66-kDa C-terminal fragment of nadrin-102 and nadrin-116 localized to the nucleus, and NGF-induced differentiation accelerated this nuclear translocation.\",\n      \"method\": \"Splice variant identification, PC12 cell neurite outgrowth assay with GAP-mutants, subcellular fractionation and localization\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — isoform-specific functional assays with GAP-activity mutants and localization data, single lab\",\n      \"pmids\": [\"12358749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The BAR domain of RICH-1 (ARHGAP17) binds membrane lipids and deforms spherical liposomes into striated tubes, consistent with oligomerization via a coiled-coil region within the BAR domain. RICH-1 forms oligomers in the presence of the chemical cross-linker BS3.\",\n      \"method\": \"Liposome tubulation assay, lipid-binding assay, chemical crosslinking (BS3)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical assays with lipid binding and crosslinking, single lab, two orthogonal methods\",\n      \"pmids\": [\"15240152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RICH1 (ARHGAP17) binds the scaffolding protein angiomotin (Amot), which targets RICH1 to a tight junction complex containing Pals1, Patj, and Par-3. Regulation of Cdc42 by RICH1 is necessary for maintenance of tight junctions in MDCK epithelial cells. The coiled-coil domain of Amot, required for Rich1 binding, is also necessary for Amot localization to apical membranes and for Amot to relocalize Pals1 and Par-3 to internal puncta.\",\n      \"method\": \"Proteomic screen (functional and protein interaction), Co-IP, MDCK cell tight junction assays, domain-deletion experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic screen confirmed by Co-IP, domain-mapping, and functional TJ-maintenance assay in epithelial cells\",\n      \"pmids\": [\"16678097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nadrin (ARHGAP17) is present in platelets where it co-localizes with actin-rich regions and Rho GTPases. Different Nadrin isoforms selectively regulate RhoA, Cdc42, or Rac1. The BAR domain controls Nadrin-GAP activity and directs the GAP to the plasma membrane. Nadrin overexpression strongly reduced platelet cell adhesion on fibrinogen and controls RhoA-mediated stress fiber and focal adhesion formation.\",\n      \"method\": \"Isoform-specific overexpression, Rho GTPase activity assays, co-localization, spreading/adhesion assay on fibrinogen, BAR domain deletion\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple isoform-specific functional assays with GTPase activity readouts, single lab\",\n      \"pmids\": [\"22975681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NADRIN (ARHGAP17) expression increased in stellate astrocytes. Induced expression accelerated morphological differentiation of cultured astrocytes into stellate cells in a GAP-activity-dependent manner. NADRIN formed a dimer via amino- and carboxy-terminal domain interaction, which was disrupted by inductive signals (dibutyryl-cAMP, EGF). Upon inductive signals, NADRIN formed a complex with ERM proteins via ERM-binding phosphoprotein 50 (EBP50) through its C-terminal PDZ-binding motif, where it inactivates RhoA.\",\n      \"method\": \"Immunoprecipitation (co-IP), GAP-activity mutant rescue, astrocyte stellation assay, domain-deletion analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP with domain mapping and GAP-mutant functional assay, single lab\",\n      \"pmids\": [\"23355722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nadrin (ARHGAP17) becomes tyrosine-phosphorylated upon platelet activation by Src family kinases (Src, Lyn, Fyn). Phosphorylation leads to isoform- and target-specific regulation: Src-phosphorylation of Nadrin5 mediates Cdc42 inactivation, while Src-phosphorylation of Nadrin2 leads to RhoA and Rac1 activation.\",\n      \"method\": \"Platelet activation assay, kinase co-IP, phosphorylation assays with Src-family inhibitors, isoform-specific Rho GTPase activity assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — kinase identification with GTPase-activity readout, isoform-specific analysis, single lab\",\n      \"pmids\": [\"24703939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PKA and PKG phosphorylate ARHGAP17 at serine 702 in platelets, which is mapped using Phos-tag gels. ARHGAP17 binds CIP4 in platelets and Ser-702 phosphorylation interferes with CIP4 binding; reduced CIP4 binding results in enhanced inhibition of cell migration by ARHGAP17. PKA/PKG activation reduces Rac1-GTP levels, and ARHGAP17 is identified as a Rac1-specific GAP mediating this effect.\",\n      \"method\": \"Phos-tag gel phosphorylation mapping, Co-IP/pulldown of ARHGAP17-CIP4 complex, Rac1-GTP assay (pull-down), cell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct phosphorylation site mapping by Phos-tag plus functional Co-IP and cell migration assay, multiple orthogonal methods\",\n      \"pmids\": [\"26507661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rich1 (ARHGAP17) overexpression in hepatocyte HL7702 epithelial cells causes S-phase arrest, proliferation inhibition, and adhesion decline with decreased F-actin. Rich1 stimulates GTP hydrolysis on both CDC42 and RAC1, attenuating their activity and the phosphorylation of PAK1 and ERK1/2. GAP-domain-deleted Rich1 or Rich1 silencing abolished all these effects, establishing a CDC42/RAC1-PAK1-ERK1/2 signaling axis.\",\n      \"method\": \"Overexpression/knockdown, Rho GTPase activity assay (GTP hydrolysis), phosphorylation (Western blot), cell cycle analysis, adhesion assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — GAP-domain deletion mutant plus GTPase activity and signaling phosphorylation readouts, single lab\",\n      \"pmids\": [\"26004135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Arhgap17-deficient mice show increased paracellular permeability and aberrant localization of the apical junction complex in intestinal luminal epithelium, establishing a role for Arhgap17 in regulating transcellular transport and maintaining intestinal barrier integrity in vivo.\",\n      \"method\": \"Knockout mouse model, paracellular permeability assay, immunofluorescence localization of apical junction complex\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout model with specific epithelial barrier and junction localization readouts, multiple assays\",\n      \"pmids\": [\"27229483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VEGF long isoform acting through NRP1 controls filopodia formation and cell migration of breast cancer cells by modulating Cdc42 activity via ARHGAP17. Genome-wide expression profiling identified ARHGAP17 as a target gene downstream of the VEGF/NRP1 signal, and VEGF knockout or soluble NRP1 overexpression impaired cell migration concordantly with altered ARHGAP17 expression and Cdc42 activity.\",\n      \"method\": \"VEGF knockout, soluble NRP1 overexpression, genome-wide expression profiling, Cdc42 activity assay, filopodia imaging\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic loss-of-function with Cdc42 activity assay and filopodia imaging, single lab\",\n      \"pmids\": [\"29971782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARHGAP17 overexpression in colon cancer cells inhibits cell growth and invasion and restricts lung metastasis in vivo. Mechanistically, ARHGAP17 increases phosphorylation of GSK3β and decreases β-catenin nuclear localization and transcriptional activity. WIF-1-mediated inhibition of Wnt signaling attenuated the proliferation/invasion promotion caused by ARHGAP17 knockdown, placing ARHGAP17 upstream of Wnt/β-catenin.\",\n      \"method\": \"Overexpression/knockdown, in vivo metastasis model, Western blot for β-catenin/GSK3β phosphorylation, GSEA, Wnt inhibitor epistasis\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis with WIF-1 plus in vivo model and signaling phosphorylation data, single lab\",\n      \"pmids\": [\"29730655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARHGAP17 overexpression abolished pathological cyclic strain-induced apoptosis in human periodontal ligament fibroblasts by inactivating Rac1/Cdc42. Rac1 inhibitors (NSC23766, EHT 1864) attenuated ARHGAP17 knockdown-mediated apoptosis, confirming epistatic placement of ARHGAP17 upstream of Rac1/Cdc42 in the apoptosis pathway.\",\n      \"method\": \"Cyclic strain model, overexpression/knockdown, Rac1/Cdc42 activity assay, pharmacological inhibition epistasis, apoptosis assay\",\n      \"journal\": \"Clinical and experimental pharmacology & physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pharmacological epistasis plus GTPase activity assay, single lab\",\n      \"pmids\": [\"32391922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARHGAP17 is a Cdc42-specific RhoGAP that localizes to the invadopodia ring during assembly, restricting Cdc42 activity to the invadopodia core. During disassembly, ARHGAP17 translocates from the ring to the core in a process mediated by its interaction with the Cdc42 effector CIP4. Once at the core, ARHGAP17 inactivates Cdc42 to promote invadopodia disassembly, defining a spatiotemporal regulatory mechanism for Cdc42 at invadopodia.\",\n      \"method\": \"Live imaging, FRAP/localization at invadopodia, Cdc42 activity biosensor (FRET-based), knockdown, Co-IP with CIP4\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — live imaging of spatiotemporal localization combined with Cdc42 activity biosensor, Co-IP with CIP4, and functional KD assays\",\n      \"pmids\": [\"36571786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RICH1 (ARHGAP17) activates the Hippo kinase cascade in breast cancer cells by competing with Merlin for binding to Amot-p80. This competition is mediated by the BAR domain of RICH1; deletion of the BAR domain abolished RICH1's ability to displace Amot-p80 from Merlin. Loss of RICH1 promoted stemness and disrupted epithelial architecture.\",\n      \"method\": \"Co-IP (RICH1-Amot-p80-Merlin complex), BAR domain deletion mutant, Hippo pathway kinase activity (MST1/2, LATS), stemness assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain-deletion mutant and functional Hippo-kinase readout, single lab\",\n      \"pmids\": [\"35064101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARHGAP17 knockdown in colon cancer cells led to elevated active Rac1 levels, while ARHGAP17 overexpression reduced active Rac1 and sensitized 5-FU-resistant cells to apoptosis. Rac1 inhibitor abolished the anti-apoptotic effect of ARHGAP17 knockdown, and Rac1 overexpression reversed the pro-apoptotic effect of ARHGAP17 overexpression, placing ARHGAP17 upstream of Rac1 in the apoptosis pathway.\",\n      \"method\": \"Rac1-GTP pull-down assay, overexpression/knockdown, pharmacological Rac1 inhibition epistasis, apoptosis (cleaved caspase-3, PARP), in vivo xenograft\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — GTPase activity assay plus pharmacological epistasis with in vivo confirmation, single lab\",\n      \"pmids\": [\"35293764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Wdr4, a substrate adaptor of the CUL4 E3 ligase complex, induces ubiquitination and degradation of Arhgap17 in cerebellar granule neuron progenitors (GNPs), thereby activating Rac1 and facilitating cell cycle progression. Loss of Wdr4 in GNPs increased Arhgap17 levels, reduced Rac1 activity, and caused proliferation defects and cerebellar developmental abnormalities.\",\n      \"method\": \"Genetic mouse KO, ubiquitination assay, Rac1-GTP pull-down, cell cycle analysis, cerebellar immunohistology\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay combined with Rac1 activity assay and in vivo KO phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"36681682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RICH1 (ARHGAP17) facilitates ubiquitination-mediated degradation of RhoA by binding TRIM21 E3 ligase and enhancing TRIM21-RhoA interaction in breast cancer cells. This leads to decreased STAT3 phosphorylation, increased IFN-γ production/secretion, and promotion of M1-like macrophage polarization.\",\n      \"method\": \"Co-IP (RICH1-TRIM21-RhoA complex), ubiquitination assay, STAT3 phosphorylation Western blot, cytokine secretion assay, macrophage polarization assay\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP complex identification with ubiquitination assay and downstream signaling readout, single lab\",\n      \"pmids\": [\"41436617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NME1, whose histidine phosphorylation is required for its activity, modulates CDC42 activity via ARHGAP17, thereby influencing cytoskeletal organization and Hippo pathway activation. Loss of NME1 reduced YAP phosphorylation and promoted YAP nuclear localization, consistent with suppression of Hippo signaling through the NME1-ARHGAP17-CDC42-cytoskeleton axis. Identified using PhastID-based proximity labeling.\",\n      \"method\": \"PhastID proximity labeling, CDC42 activity assay, YAP phosphorylation/localization assay, loss-of-function\",\n      \"journal\": \"Life medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — proximity labeling combined with GTPase activity and Hippo pathway readout, single lab, single study\",\n      \"pmids\": [\"41978798\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARHGAP17 (also known as RICH1/NADRIN) is a BAR-domain-containing RhoGAP that inactivates Cdc42, Rac1, and RhoA in a context- and isoform-dependent manner; it is regulated by PKA/PKG phosphorylation at Ser-702 (disrupting CIP4 binding), by Src-family-mediated tyrosine phosphorylation (isoform-specific GTPase targeting), and by CUL4-Wdr4-mediated ubiquitination/degradation; it maintains epithelial tight junction integrity via an Amot scaffold complex, controls invadopodia turnover by spatiotemporally restricting Cdc42 activity in a CIP4-dependent manner, activates Hippo signaling by competing with Merlin for Amot-p80 binding, and connects upstream NME1 histidine-phosphorylation to the CDC42-cytoskeleton-Hippo axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARHGAP17 (RICH1/NADRIN) is a BAR-domain–containing RhoGAP that inactivates the Rho-family GTPases Cdc42, Rac1, and RhoA to control actin cytoskeletal remodeling, epithelial junction integrity, and downstream proliferative and morphogenetic signaling [#0, #8]. Its N-terminal BAR domain binds and tubulates membrane lipids, directing GAP activity to the plasma membrane and supporting oligomerization [#2, #4], and its GAP activity is required for its cellular effects on actin organization, neurite outgrowth, astrocyte stellation, and exocytosis [#0, #2, #5]. At epithelial tight junctions ARHGAP17 is recruited by the scaffold angiomotin (Amot) into a Pals1/Patj/Par-3 complex where it locally regulates Cdc42 to maintain junction integrity, a role confirmed in vivo by intestinal barrier defects in knockout mice [#3, #9]. At invadopodia it is spatiotemporally repositioned from the ring to the core via its Cdc42 effector partner CIP4, restricting Cdc42 activity to drive structure disassembly [#13]. Through its BAR domain it competes with Merlin for Amot-p80 binding to activate the Hippo kinase cascade and restrain stemness [#14], and it links the NME1–CDC42–cytoskeleton axis to Hippo/YAP regulation [#18]. ARHGAP17 activity is tuned by PKA/PKG phosphorylation at Ser-702, which disrupts CIP4 binding [#7], by Src-family tyrosine phosphorylation that switches its isoform-specific GTPase targeting [#6], and by CUL4-Wdr4–mediated ubiquitination and degradation [#16]; it also scaffolds TRIM21-dependent ubiquitination of RhoA [#17]. Across cancer models ARHGAP17 acts as a growth- and invasion-suppressing GAP upstream of Rac1/Cdc42-PAK1-ERK and Wnt/β-catenin signaling [#8, #11, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that ARHGAP17/NADRIN is a functional RhoGAP whose catalytic activity drives actin remodeling and regulated exocytosis, defining its core molecular identity.\",\n      \"evidence\": \"In vitro GAP assay against RhoA/Rac1/Cdc42 plus domain-deletion mutants in NIH3T3 and PC12 cells with exocytosis readout\",\n      \"pmids\": [\"10967100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GTPase target specificity in vivo not resolved\", \"structural basis of GAP activity not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that alternative splicing produces functionally distinct isoforms with isoform-specific effects on neurite outgrowth and nuclear translocation of a C-terminal fragment, indicating isoform-encoded functional diversity.\",\n      \"evidence\": \"Splice variant identification with GAP-mutant neurite outgrowth assays and subcellular fractionation in PC12 cells\",\n      \"pmids\": [\"12358749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"function of the nuclear C-terminal fragment unknown\", \"single-lab isoform characterization\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that the BAR domain binds and deforms membranes and mediates oligomerization, providing the structural basis for membrane targeting of the GAP.\",\n      \"evidence\": \"Liposome tubulation, lipid-binding, and BS3 crosslinking assays in vitro\",\n      \"pmids\": [\"15240152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"lipid species preference not mapped\", \"in-cell consequences of tubulation untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the Amot scaffold as the recruiter of ARHGAP17 to a tight junction complex, explaining how Cdc42 regulation is spatially restricted to maintain epithelial junctions.\",\n      \"evidence\": \"Proteomic screen, Co-IP, domain mapping, and tight junction maintenance assays in MDCK cells\",\n      \"pmids\": [\"16678097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism of GAP activation within the complex unknown\", \"direct vs indirect Amot binding not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that distinct isoforms selectively target RhoA, Cdc42, or Rac1 and that the BAR domain controls both membrane localization and GAP activity in platelets, linking isoform identity to GTPase choice.\",\n      \"evidence\": \"Isoform-specific overexpression, GTPase activity assays, BAR deletion, and fibrinogen adhesion assays in platelets\",\n      \"pmids\": [\"22975681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"determinants of isoform-specific GTPase selectivity unclear\", \"single-lab characterization\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that signal-induced conformational change releases an autoinhibitory dimer and routes ARHGAP17 to ERM/EBP50 complexes to inactivate RhoA during astrocyte stellation, revealing a regulated activation switch.\",\n      \"evidence\": \"Co-IP, domain-deletion analysis, GAP-mutant rescue, and stellation assays in cultured astrocytes\",\n      \"pmids\": [\"23355722\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis of intramolecular dimer not defined\", \"signal-to-conformation coupling not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined PKA/PKG phosphorylation at Ser-702 as a regulatory switch that disrupts CIP4 binding and enhances Rac1-specific inhibition of migration, connecting cyclic-nucleotide signaling to GAP function.\",\n      \"evidence\": \"Phos-tag site mapping, ARHGAP17-CIP4 Co-IP, Rac1-GTP pulldown, and migration assays in platelets\",\n      \"pmids\": [\"26507661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how CIP4 binding gates GAP activity not fully mechanistic\", \"Ser-702 role outside platelets untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed ARHGAP17 upstream of a CDC42/RAC1-PAK1-ERK1/2 axis controlling proliferation and adhesion, linking its GAP activity to mitogenic signaling output.\",\n      \"evidence\": \"Overexpression/knockdown, GTPase activity assays, phospho-Western, and cell cycle/adhesion assays in HL7702 hepatocytes\",\n      \"pmids\": [\"26004135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct vs indirect effect on PAK1/ERK not separated\", \"single cell line\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed that Src-family tyrosine phosphorylation switches isoform-specific GTPase targeting, adding a kinase-controlled layer to ARHGAP17 output during platelet activation.\",\n      \"evidence\": \"Platelet activation, kinase Co-IP, Src-family inhibitor phosphorylation assays, and isoform-specific GTPase activity assays\",\n      \"pmids\": [\"24703939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"phosphosite identities not mapped\", \"mechanism converting RhoGAP to GTPase-activating output unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided in vivo proof that ARHGAP17 maintains intestinal epithelial barrier integrity through proper apical junction localization, validating the cell-based tight junction model.\",\n      \"evidence\": \"Arhgap17 knockout mouse with paracellular permeability and junction immunofluorescence\",\n      \"pmids\": [\"27229483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GTPase responsible for the in vivo phenotype not pinned down\", \"tissue-specific contribution not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned ARHGAP17 as a tumor-suppressing GAP downstream of VEGF/NRP1 and upstream of Wnt/β-catenin, connecting its Cdc42/Rac1 control to cancer cell migration and metastasis.\",\n      \"evidence\": \"VEGF KO/soluble NRP1, expression profiling, Cdc42 activity and filopodia imaging; plus overexpression/knockdown, in vivo metastasis, and WIF-1 epistasis in colon cancer\",\n      \"pmids\": [\"29971782\", \"29730655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanistic link from GAP activity to β-catenin/GSK3β not direct\", \"single-lab models\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established spatiotemporal control of Cdc42 at invadopodia, showing CIP4-mediated ring-to-core translocation of ARHGAP17 drives structure disassembly, a high-resolution mechanistic picture of its GAP function.\",\n      \"evidence\": \"Live imaging, Cdc42 FRET biosensor, knockdown, and CIP4 Co-IP at invadopodia\",\n      \"pmids\": [\"36571786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"upstream signal triggering translocation unknown\", \"general applicability beyond invadopodia untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a BAR-domain-dependent competition with Merlin for Amot-p80 that activates the Hippo cascade and restrains stemness, linking ARHGAP17 to Hippo regulation in addition to GTPase control.\",\n      \"evidence\": \"Co-IP of RICH1-Amot-p80-Merlin, BAR deletion, MST/LATS activity, and stemness assays in breast cancer cells\",\n      \"pmids\": [\"35064101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether Hippo effect is GAP-independent not fully resolved\", \"single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed ARHGAP17 acts upstream of Rac1 to control apoptosis and chemoresistance, reinforcing its GAP-dependent role in cancer cell survival across stress contexts.\",\n      \"evidence\": \"Rac1-GTP pulldown, pharmacological epistasis, apoptosis markers, and xenograft in colon cancer; cyclic-strain apoptosis model in periodontal fibroblasts\",\n      \"pmids\": [\"35293764\", \"32391922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"downstream apoptotic effectors of Rac1 not specified\", \"single-lab models\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified CUL4-Wdr4–mediated ubiquitination and degradation as a mechanism controlling ARHGAP17 abundance, thereby gating Rac1 activity and neural progenitor proliferation in vivo.\",\n      \"evidence\": \"Wdr4 mouse KO, ubiquitination assay, Rac1-GTP pulldown, and cerebellar histology\",\n      \"pmids\": [\"36681682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ubiquitination sites on ARHGAP17 not mapped\", \"signals regulating Wdr4-ARHGAP17 axis unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed ARHGAP17 scaffolds TRIM21-dependent ubiquitination of RhoA, coupling GTPase degradation to STAT3 suppression and M1 macrophage polarization, extending its function into immune regulation.\",\n      \"evidence\": \"Co-IP of RICH1-TRIM21-RhoA, ubiquitination assay, STAT3 phospho-Western, cytokine and macrophage polarization assays in breast cancer\",\n      \"pmids\": [\"41436617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether scaffolding is GAP-activity-dependent unclear\", \"single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected NME1 histidine-phosphorylation to ARHGAP17-CDC42 control of the cytoskeleton and Hippo/YAP signaling, placing ARHGAP17 within an upstream metabolic-kinase input.\",\n      \"evidence\": \"PhastID proximity labeling, CDC42 activity assay, and YAP phosphorylation/localization with NME1 loss-of-function\",\n      \"pmids\": [\"41978798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct NME1-ARHGAP17 interaction vs proximity not distinguished\", \"single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How isoform identity, post-translational modification, scaffold binding, and degradation are integrated to determine which GTPase ARHGAP17 acts on in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unified structural model of GTPase selectivity\", \"interplay of Ser-702, Tyr phosphorylation, and ubiquitination not co-analyzed\", \"in vivo isoform-specific functions largely untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 8, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 14, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8, 14]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 15]}\n    ],\n    \"complexes\": [\"Amot tight junction complex (Pals1/Patj/Par-3)\"],\n    \"partners\": [\"AMOT\", \"CIP4\", \"TRIM21\", \"EBP50\", \"NME1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}