{"gene":"RASIP1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2004,"finding":"RASIP1 (Rain/Rasip1) interacts with Ras in a GTP-dependent manner in vitro and in vivo, requires an intact Ras core effector-binding domain for this interaction, and localizes to perinuclear, juxta-Golgi vesicles in intact cells; activated Ras recruits Rasip1 to the Golgi. Rasip1 cooperates with activated Raf to cause synergistic transformation of NIH3T3 cells, consistent with a role as a Ras effector at endomembranes.","method":"Co-IP, in vitro binding assays, live-cell imaging/immunofluorescence localization, NIH3T3 transformation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays (in vitro and in vivo), subcellular localization experiment, and functional transformation assay in a single lab study","pmids":["15031288"],"is_preprint":false},{"year":2009,"finding":"siRNA-mediated knockdown of Rasip1 in endothelial cell cultures severely impairs angiogenesis and cell motility; morpholino knockdown in Xenopus embryos demonstrates that Rasip1 is required for embryonic vessel formation in vivo, establishing an endothelial-specific role in vascular development.","method":"siRNA knockdown in cultured endothelial cells (angiogenesis/motility assays), morpholino knockdown in Xenopus embryos","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in two orthogonal model systems (cell culture and in vivo), single lab","pmids":["19272373"],"is_preprint":false},{"year":2011,"finding":"Rasip1 null mice fail to form patent vascular lumens in all blood vessels. Rasip1 acts through its binding partner RhoGAP Arhgap29 to suppress RhoA/ROCK/myosin II activity and promote Cdc42 and Rac1 signaling. Loss of Rasip1 or Arhgap29 in cultured ECs blocks lumen formation, alters cytoskeletal organization, and reduces integrin-dependent ECM adhesion. Rasip1 null angioblasts fail to properly localize the polarity determinant Par3.","method":"Rasip1 knockout mice, siRNA depletion of Rasip1/Arhgap29 in cultured ECs, in vitro lumen formation assay, RhoA/Cdc42/Rac1 activity assays, immunofluorescence","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout phenotype combined with multiple orthogonal in vitro mechanistic assays identifying pathway components (RhoA, Cdc42, Rac1, Arhgap29, Par3)","pmids":["21396893"],"is_preprint":false},{"year":2013,"finding":"Rasip1 is a direct Rap1 effector: FRET experiments show Rasip1 interacts with active Rap1 in a cellular context. Rasip1 mediates Rap1-induced cell spreading by engaging its binding partner ArhGAP29 to inhibit Rho signaling. The Rasip1–ArhGAP29 pathway operates in Rap1-mediated regulation of endothelial junctions and endothelial barrier function, suppressing Rho-mediated stress fiber formation.","method":"FRET-based interaction assay, siRNA knockdown, cell spreading assays, endothelial barrier permeability assays, Rho activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — FRET directly demonstrates Rap1–Rasip1 interaction in cells; multiple orthogonal functional assays confirming ArhGAP29-mediated Rho inhibition downstream of Rap1","pmids":["23798437"],"is_preprint":false},{"year":2013,"finding":"Endogenous RASIP1 in endothelial cells binds RAP1 (but not RhoA or Cdc42 directly). RASIP1 localizes to nascent cell-cell contacts in an EPAC1-RAP1-dependent manner. Loss of RASIP1 alters junctional actin organization and localization of nonmuscle myosin heavy chain IIB, and phenocopies loss of RAP1 or EPAC1, placing RASIP1 as an effector of the EPAC1–RAP1 pathway at endothelial junctions.","method":"Co-IP of endogenous proteins, immunofluorescence localization, siRNA knockdown, EPAC1-RAP1 junction-formation model in ECs, zebrafish/mouse embryo analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous co-IP, in vivo vertebrate models (mouse and zebrafish), and multiple cellular assays establishing pathway position","pmids":["23886837"],"is_preprint":false},{"year":2016,"finding":"HEG1 (Heart of Glass) directly binds a central region of Rasip1 and is required to recruit Rasip1 to endothelial cell–cell junctions. Proteomic screen identified HEG1 as a Rasip1 interactor; mitochondria-targeted HEG1 relocalizes Rasip1 to mitochondria. A 9-residue sequence in HEG1 is necessary for Rasip1 binding; deletion of the HEG1-binding domain in Rasip1 eliminates junctional localization, ROCK inhibition, and EC junctional integrity.","method":"Proteomic screen for HEG1 interactors, direct binding assays, mitochondrial-targeting relocalization experiment, deletion mutagenesis, ROCK activity assay, EC junction integrity assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding established by proteomic screen plus mutagenesis, and functional consequences confirmed by relocalization experiment and ROCK/junction assays","pmids":["26780829"],"is_preprint":false},{"year":2016,"finding":"Rasip1 controls distinct GTPase pools during vascular tubulogenesis: (1) Rasip1 promotes Cdc42 activity, which activates Pak4, leading to nonmuscle myosin II (NMII) activation and clearance of apical junctions during lumen opening; (2) once lumens open, Rasip1 suppresses RhoA via Arhgap29, inhibiting actomyosin contractility to allow controlled vessel expansion. Conditional mouse mutants and pharmacological inhibition of Pak4 or NMII confirm these stepwise roles.","method":"Conditional mouse knockout of Rasip1 and Cdc42, pharmacological inhibition of Pak4 and NMII, epistasis analysis, immunofluorescence","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic models with epistasis analysis and pharmacological dissection, multiple orthogonal approaches defining pathway hierarchy","pmids":["27486147"],"is_preprint":false},{"year":2016,"finding":"Rasip1 is required for angiogenesis (in vitro matrix invasion, postnatal retinal vessel growth, directed in vivo angiogenesis) but is dispensable for maintenance of established quiescent adult blood vessels, demonstrating a context-dependent requirement.","method":"Conditional endothelial-specific Rasip1 knockout mouse, retinal angiogenesis assay, directed in vivo angiogenesis assay, in vitro matrix invasion assay","journal":"Angiogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo genetic models and angiogenesis assays establishing context-dependent requirement","pmids":["26897025"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the Rasip1 RA domain (RRA) was solved alone and in complex with Rap1 at 2.8 Å resolution. RRA forms a dimer that binds two Rap1 (KD = 0.9 μM) or Ras (KD = 2.2 μM) molecules. Rasip1 contacts Rap1 in the Switch I region; Rap1 binding stabilizes a β strand and an unstructured loop. This defines Rasip1 as a member of a subgroup of dimeric RA domains capable of cooperative binding to membrane-associated Ras superfamily members.","method":"X-ray crystallography (crystal structure), isothermal titration calorimetry or equivalent binding affinity measurements","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.8 Å with quantitative binding measurements, rigorous structural study","pmids":["27839947"],"is_preprint":false},{"year":2018,"finding":"Lymphatic endothelial cell-specific deletion of Rasip1 in mice causes enlarged, blood-filled lymphatics with disorganized junctions and, at later stages, fragmented lumens and defective lymphatic valve formation. Rasip1 regulates Cdc42 activity in lymphatic ECs; ectopic Cdc42 expression rescues the Rasip1-deficient phenotype, placing Rasip1 upstream of Cdc42 in lymphatic lumen maintenance and junction organization.","method":"Lymphatic EC-specific conditional Rasip1 knockout mouse, in vitro junction/cytoskeleton assays, Cdc42 activity assay, Cdc42 rescue experiment","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional in vivo knockout with genetic rescue by Cdc42 expression, establishing epistatic relationship","pmids":["30042182"],"is_preprint":false},{"year":2018,"finding":"RUNX1 directly binds the Rasip1 promoter at a specific DNA sequence (demonstrated by ChIP and luciferase reporter assay) and activates Rasip1 transcription. Silencing Rasip1 inhibits the migration of RUNX1-overexpressing NSCLC cells through inactivation of the Rac1 pathway. EGFR signaling regulates both expression and subcellular localization of Rasip1 in lung cancer cells.","method":"ChIP with anti-RUNX1 antibody, luciferase reporter assay, siRNA knockdown, transwell/wound-healing migration assays, Rac1 activity assay, immunofluorescence","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirm direct transcriptional regulation; functional migration assays with pathway readout; single lab","pmids":["30349386"],"is_preprint":false},{"year":2021,"finding":"In zebrafish rasip1 mutants, Rasip1 is required for: (1) stabilization of tricellular junctions during angiogenic sprouting to maintain multicellular organization; (2) establishment of a stable apical membrane compartment during anastomosis (loss causes ectopic reticulated junctions and collapsed apical compartment). Loss of Ccm1 and Heg1 phenocopies rasip1 junction defects; downregulation of ccm1 and heg1 delocalizes Rasip1 from cell junctions, placing Rasip1 downstream of the Ccm1–Heg1 complex for junctional tethering.","method":"Zebrafish rasip1 genetic mutants, live imaging of F-actin and junction dynamics, epistasis analysis with ccm1 and heg1 morphants/mutants, immunofluorescence","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mutants in zebrafish with live imaging and epistasis analysis across multiple pathway components","pmids":["34383884"],"is_preprint":false}],"current_model":"RASIP1 is an endothelial-specific adaptor protein that functions as an effector of the EPAC1–RAP1 and RAS GTPase signaling axes; it is recruited to endothelial cell–cell junctions via direct binding to the transmembrane receptor HEG1 (which requires Ccm1), where its dimeric RA domain engages active RAP1 (KD ~0.9 μM) or RAS, and it coordinates vascular lumenogenesis by sequentially activating CDC42–PAK4–nonmuscle myosin II to clear apical junctions during lumen opening, and then suppressing RhoA contractility through its constitutive binding partner ARHGAP29, thereby permitting controlled vessel expansion and maintaining endothelial barrier integrity."},"narrative":{"mechanistic_narrative":"RASIP1 is an endothelial-enriched adaptor protein that links Ras-superfamily GTPase signaling to the control of vascular lumen formation, endothelial junction organization, and angiogenesis [PMID:21396893, PMID:26897025]. It functions as a direct effector of RAP1 and RAS: its RA domain forms a dimer that binds two molecules of active RAP1 (KD ~0.9 μM) or RAS (KD ~2.2 μM) at the GTPase Switch I region, defining it as a cooperative, membrane-associated GTPase sensor [PMID:27839947], and it is recruited to nascent endothelial cell–cell contacts in an EPAC1–RAP1-dependent manner [PMID:23886837]. Junctional tethering requires the transmembrane receptor HEG1, which binds a central region of RASIP1 and acts downstream of the Ccm1–Heg1 complex to localize RASIP1 to junctions; deletion of the HEG1-binding region abolishes junctional localization, ROCK inhibition, and barrier integrity [PMID:26780829, PMID:34383884]. At the junction RASIP1 coordinates opposing GTPase pools during tubulogenesis: it activates a CDC42–PAK4–nonmuscle myosin II module to clear apical junctions during lumen opening, and then suppresses RhoA/ROCK/myosin II contractility through its partner ARHGAP29 to permit controlled vessel expansion and maintain barrier function [PMID:23798437, PMID:27486147]. This activity is required for blood and lymphatic vessel lumenogenesis, tricellular and apical junction stability, and angiogenic sprouting, while being dispensable for established quiescent vessels [PMID:21396893, PMID:26897025, PMID:30042182, PMID:34383884].","teleology":[{"year":2004,"claim":"Established that RASIP1 is a GTP-dependent Ras effector, answering whether it physically and functionally couples to active Ras.","evidence":"Co-IP, in vitro binding requiring an intact Ras effector domain, juxta-Golgi localization, and synergistic NIH3T3 transformation with activated Raf","pmids":["15031288"],"confidence":"Medium","gaps":["Did not connect Ras binding to a vascular function","Endomembrane localization not reconciled with later junctional localization","No structural basis for the interaction"]},{"year":2009,"claim":"Demonstrated that RASIP1 is required for vessel formation, defining an endothelial-specific developmental role beyond cultured-cell transformation.","evidence":"siRNA knockdown in cultured endothelial cells and morpholino knockdown in Xenopus embryos","pmids":["19272373"],"confidence":"Medium","gaps":["Molecular mechanism of the vascular requirement undefined","GTPase effector linkage to the phenotype not established"]},{"year":2011,"claim":"Defined the core mechanism: RASIP1 controls vascular lumen formation by partnering with the RhoGAP ARHGAP29 to suppress RhoA/ROCK/myosin II and promote Cdc42/Rac1.","evidence":"Rasip1 knockout mice, EC siRNA depletion, in vitro lumen assays, RhoA/Cdc42/Rac1 activity assays, Par3 localization","pmids":["21396893"],"confidence":"High","gaps":["Upstream GTPase activating RASIP1 not identified","Mechanism recruiting RASIP1 to membranes/junctions unknown"]},{"year":2013,"claim":"Identified RAP1 as the activating GTPase and placed RASIP1 within the EPAC1–RAP1 pathway controlling endothelial junctions and barrier function.","evidence":"FRET interaction with active Rap1, endogenous Co-IP, EPAC1-RAP1 junction-formation model, barrier permeability and Rho activity assays, zebrafish/mouse analysis","pmids":["23798437","23886837"],"confidence":"High","gaps":["How RAP1 binding translates to ARHGAP29 regulation mechanistically unclear","Structural basis of Rap1 recognition not resolved"]},{"year":2016,"claim":"Established the junctional recruitment mechanism and the stepwise GTPase logic, showing HEG1 tethers RASIP1 to junctions and RASIP1 sequentially drives CDC42-PAK4-NMII then ARHGAP29-mediated RhoA suppression.","evidence":"HEG1 proteomic screen, direct binding and mitochondrial relocalization, deletion mutagenesis, conditional Rasip1/Cdc42 knockouts, Pak4/NMII pharmacology, ROCK and junction assays","pmids":["26780829","27486147","26897025"],"confidence":"High","gaps":["How a single adaptor temporally switches between opposing GTPase pools is not fully resolved","Requirement is context-dependent (angiogenesis vs quiescent vessels) by unknown determinants"]},{"year":2016,"claim":"Provided the structural basis for RASIP1 acting as a cooperative GTPase sensor, showing its RA domain dimerizes to bind two RAP1 or RAS molecules at Switch I.","evidence":"X-ray crystallography of the RRA domain alone and with Rap1 at 2.8 Å, with quantitative affinity measurements (Rap1 KD 0.9 μM, Ras KD 2.2 μM)","pmids":["27839947"],"confidence":"High","gaps":["Functional consequence of cooperative dimeric binding in cells not directly tested","Selectivity between Rap1 and Ras in vivo not resolved"]},{"year":2018,"claim":"Extended RASIP1 function to the lymphatic system and confirmed CDC42 as a key downstream effector via genetic rescue.","evidence":"Lymphatic EC-specific conditional knockout, junction/cytoskeleton assays, Cdc42 activity assay, Cdc42 rescue of the deficient phenotype","pmids":["30042182"],"confidence":"High","gaps":["Whether lymphatic and blood vessel mechanisms are identical not established","Role in valve formation mechanistically undefined"]},{"year":2018,"claim":"Revealed transcriptional and growth-factor control of RASIP1 and a role in cancer cell migration, broadening its context beyond vascular development.","evidence":"ChIP and luciferase reporter showing RUNX1 binds the Rasip1 promoter, siRNA, migration assays, Rac1 activity, EGFR-dependent expression/localization in NSCLC cells","pmids":["30349386"],"confidence":"Medium","gaps":["Generality of RUNX1/EGFR regulation across cell types unknown","Single-lab cancer migration link not independently confirmed"]},{"year":2021,"claim":"Defined RASIP1's role in junction subcellular architecture and confirmed its dependence on the Ccm1–Heg1 complex for junctional localization.","evidence":"Zebrafish rasip1 mutants with live imaging of F-actin/junctions and epistasis with ccm1 and heg1","pmids":["34383884"],"confidence":"High","gaps":["Molecular steps linking junctional tethering to apical compartment stability unresolved","Role of Ccm1 in the HEG1-RASIP1 binding interaction not biochemically defined"]},{"year":null,"claim":"How RASIP1 temporally and spatially coordinates the switch between CDC42-driven junction clearance and ARHGAP29-mediated RhoA suppression at the molecular level remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No mechanism explaining how one adaptor sequentially activates opposing GTPase modules","Structural basis for ARHGAP29 binding and regulation not determined","Determinants of context-dependent requirement (angiogenic vs quiescent) unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,6]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,4,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,5,11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,7,9]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,4,5]}],"complexes":[],"partners":["RAP1","RAS","ARHGAP29","HEG1","CDC42"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5U651","full_name":"Ras-interacting protein 1","aliases":[],"length_aa":963,"mass_kda":103.5,"function":"Required for the proper formation of vascular structures that develop via both vasculogenesis and angiogenesis. Acts as a critical and vascular-specific regulator of GTPase signaling, cell architecture, and adhesion, which is essential for endothelial cell morphogenesis and blood vessel tubulogenesis. Regulates the activity of Rho GTPases in part by recruiting ARHGAP29 and suppressing RhoA signaling and dampening ROCK and MYH9 activities in endothelial cells (By similarity). May act as effector for Golgi-bound HRAS and other Ras-like proteins. May promote HRAS-mediated transformation. Negative regulator of amino acid starvation-induced autophagy","subcellular_location":"Cytoplasm, perinuclear region; Golgi apparatus, Golgi stack","url":"https://www.uniprot.org/uniprotkb/Q5U651/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RASIP1","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RASIP1","total_profiled":1310},"omim":[{"mim_id":"609623","title":"RAS-INTERACTING PROTEIN 1; RASIP1","url":"https://www.omim.org/entry/609623"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RASIP1"},"hgnc":{"alias_symbol":["FLJ20401","RAIN"],"prev_symbol":[]},"alphafold":{"accession":"Q5U651","domains":[{"cath_id":"3.10.20.90","chopping":"147-188_199-212_222-270","consensus_level":"high","plddt":82.2841,"start":147,"end":270},{"cath_id":"2.60.200.20","chopping":"376-411_422-492","consensus_level":"high","plddt":86.9726,"start":376,"end":492}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5U651","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5U651-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5U651-F1-predicted_aligned_error_v6.png","plddt_mean":70.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RASIP1","jax_strain_url":"https://www.jax.org/strain/search?query=RASIP1"},"sequence":{"accession":"Q5U651","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5U651.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5U651/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5U651"}},"corpus_meta":[{"pmid":"25326247","id":"PMC_25326247","title":"Detecting 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Rasip1 cooperates with activated Raf to cause synergistic transformation of NIH3T3 cells, consistent with a role as a Ras effector at endomembranes.\",\n      \"method\": \"Co-IP, in vitro binding assays, live-cell imaging/immunofluorescence localization, NIH3T3 transformation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays (in vitro and in vivo), subcellular localization experiment, and functional transformation assay in a single lab study\",\n      \"pmids\": [\"15031288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"siRNA-mediated knockdown of Rasip1 in endothelial cell cultures severely impairs angiogenesis and cell motility; morpholino knockdown in Xenopus embryos demonstrates that Rasip1 is required for embryonic vessel formation in vivo, establishing an endothelial-specific role in vascular development.\",\n      \"method\": \"siRNA knockdown in cultured endothelial cells (angiogenesis/motility assays), morpholino knockdown in Xenopus embryos\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in two orthogonal model systems (cell culture and in vivo), single lab\",\n      \"pmids\": [\"19272373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rasip1 null mice fail to form patent vascular lumens in all blood vessels. Rasip1 acts through its binding partner RhoGAP Arhgap29 to suppress RhoA/ROCK/myosin II activity and promote Cdc42 and Rac1 signaling. Loss of Rasip1 or Arhgap29 in cultured ECs blocks lumen formation, alters cytoskeletal organization, and reduces integrin-dependent ECM adhesion. Rasip1 null angioblasts fail to properly localize the polarity determinant Par3.\",\n      \"method\": \"Rasip1 knockout mice, siRNA depletion of Rasip1/Arhgap29 in cultured ECs, in vitro lumen formation assay, RhoA/Cdc42/Rac1 activity assays, immunofluorescence\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout phenotype combined with multiple orthogonal in vitro mechanistic assays identifying pathway components (RhoA, Cdc42, Rac1, Arhgap29, Par3)\",\n      \"pmids\": [\"21396893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rasip1 is a direct Rap1 effector: FRET experiments show Rasip1 interacts with active Rap1 in a cellular context. Rasip1 mediates Rap1-induced cell spreading by engaging its binding partner ArhGAP29 to inhibit Rho signaling. The Rasip1–ArhGAP29 pathway operates in Rap1-mediated regulation of endothelial junctions and endothelial barrier function, suppressing Rho-mediated stress fiber formation.\",\n      \"method\": \"FRET-based interaction assay, siRNA knockdown, cell spreading assays, endothelial barrier permeability assays, Rho activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — FRET directly demonstrates Rap1–Rasip1 interaction in cells; multiple orthogonal functional assays confirming ArhGAP29-mediated Rho inhibition downstream of Rap1\",\n      \"pmids\": [\"23798437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Endogenous RASIP1 in endothelial cells binds RAP1 (but not RhoA or Cdc42 directly). RASIP1 localizes to nascent cell-cell contacts in an EPAC1-RAP1-dependent manner. Loss of RASIP1 alters junctional actin organization and localization of nonmuscle myosin heavy chain IIB, and phenocopies loss of RAP1 or EPAC1, placing RASIP1 as an effector of the EPAC1–RAP1 pathway at endothelial junctions.\",\n      \"method\": \"Co-IP of endogenous proteins, immunofluorescence localization, siRNA knockdown, EPAC1-RAP1 junction-formation model in ECs, zebrafish/mouse embryo analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous co-IP, in vivo vertebrate models (mouse and zebrafish), and multiple cellular assays establishing pathway position\",\n      \"pmids\": [\"23886837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HEG1 (Heart of Glass) directly binds a central region of Rasip1 and is required to recruit Rasip1 to endothelial cell–cell junctions. Proteomic screen identified HEG1 as a Rasip1 interactor; mitochondria-targeted HEG1 relocalizes Rasip1 to mitochondria. A 9-residue sequence in HEG1 is necessary for Rasip1 binding; deletion of the HEG1-binding domain in Rasip1 eliminates junctional localization, ROCK inhibition, and EC junctional integrity.\",\n      \"method\": \"Proteomic screen for HEG1 interactors, direct binding assays, mitochondrial-targeting relocalization experiment, deletion mutagenesis, ROCK activity assay, EC junction integrity assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding established by proteomic screen plus mutagenesis, and functional consequences confirmed by relocalization experiment and ROCK/junction assays\",\n      \"pmids\": [\"26780829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rasip1 controls distinct GTPase pools during vascular tubulogenesis: (1) Rasip1 promotes Cdc42 activity, which activates Pak4, leading to nonmuscle myosin II (NMII) activation and clearance of apical junctions during lumen opening; (2) once lumens open, Rasip1 suppresses RhoA via Arhgap29, inhibiting actomyosin contractility to allow controlled vessel expansion. Conditional mouse mutants and pharmacological inhibition of Pak4 or NMII confirm these stepwise roles.\",\n      \"method\": \"Conditional mouse knockout of Rasip1 and Cdc42, pharmacological inhibition of Pak4 and NMII, epistasis analysis, immunofluorescence\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic models with epistasis analysis and pharmacological dissection, multiple orthogonal approaches defining pathway hierarchy\",\n      \"pmids\": [\"27486147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rasip1 is required for angiogenesis (in vitro matrix invasion, postnatal retinal vessel growth, directed in vivo angiogenesis) but is dispensable for maintenance of established quiescent adult blood vessels, demonstrating a context-dependent requirement.\",\n      \"method\": \"Conditional endothelial-specific Rasip1 knockout mouse, retinal angiogenesis assay, directed in vivo angiogenesis assay, in vitro matrix invasion assay\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo genetic models and angiogenesis assays establishing context-dependent requirement\",\n      \"pmids\": [\"26897025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the Rasip1 RA domain (RRA) was solved alone and in complex with Rap1 at 2.8 Å resolution. RRA forms a dimer that binds two Rap1 (KD = 0.9 μM) or Ras (KD = 2.2 μM) molecules. Rasip1 contacts Rap1 in the Switch I region; Rap1 binding stabilizes a β strand and an unstructured loop. This defines Rasip1 as a member of a subgroup of dimeric RA domains capable of cooperative binding to membrane-associated Ras superfamily members.\",\n      \"method\": \"X-ray crystallography (crystal structure), isothermal titration calorimetry or equivalent binding affinity measurements\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.8 Å with quantitative binding measurements, rigorous structural study\",\n      \"pmids\": [\"27839947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lymphatic endothelial cell-specific deletion of Rasip1 in mice causes enlarged, blood-filled lymphatics with disorganized junctions and, at later stages, fragmented lumens and defective lymphatic valve formation. Rasip1 regulates Cdc42 activity in lymphatic ECs; ectopic Cdc42 expression rescues the Rasip1-deficient phenotype, placing Rasip1 upstream of Cdc42 in lymphatic lumen maintenance and junction organization.\",\n      \"method\": \"Lymphatic EC-specific conditional Rasip1 knockout mouse, in vitro junction/cytoskeleton assays, Cdc42 activity assay, Cdc42 rescue experiment\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional in vivo knockout with genetic rescue by Cdc42 expression, establishing epistatic relationship\",\n      \"pmids\": [\"30042182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RUNX1 directly binds the Rasip1 promoter at a specific DNA sequence (demonstrated by ChIP and luciferase reporter assay) and activates Rasip1 transcription. Silencing Rasip1 inhibits the migration of RUNX1-overexpressing NSCLC cells through inactivation of the Rac1 pathway. EGFR signaling regulates both expression and subcellular localization of Rasip1 in lung cancer cells.\",\n      \"method\": \"ChIP with anti-RUNX1 antibody, luciferase reporter assay, siRNA knockdown, transwell/wound-healing migration assays, Rac1 activity assay, immunofluorescence\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirm direct transcriptional regulation; functional migration assays with pathway readout; single lab\",\n      \"pmids\": [\"30349386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish rasip1 mutants, Rasip1 is required for: (1) stabilization of tricellular junctions during angiogenic sprouting to maintain multicellular organization; (2) establishment of a stable apical membrane compartment during anastomosis (loss causes ectopic reticulated junctions and collapsed apical compartment). Loss of Ccm1 and Heg1 phenocopies rasip1 junction defects; downregulation of ccm1 and heg1 delocalizes Rasip1 from cell junctions, placing Rasip1 downstream of the Ccm1–Heg1 complex for junctional tethering.\",\n      \"method\": \"Zebrafish rasip1 genetic mutants, live imaging of F-actin and junction dynamics, epistasis analysis with ccm1 and heg1 morphants/mutants, immunofluorescence\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mutants in zebrafish with live imaging and epistasis analysis across multiple pathway components\",\n      \"pmids\": [\"34383884\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RASIP1 is an endothelial-specific adaptor protein that functions as an effector of the EPAC1–RAP1 and RAS GTPase signaling axes; it is recruited to endothelial cell–cell junctions via direct binding to the transmembrane receptor HEG1 (which requires Ccm1), where its dimeric RA domain engages active RAP1 (KD ~0.9 μM) or RAS, and it coordinates vascular lumenogenesis by sequentially activating CDC42–PAK4–nonmuscle myosin II to clear apical junctions during lumen opening, and then suppressing RhoA contractility through its constitutive binding partner ARHGAP29, thereby permitting controlled vessel expansion and maintaining endothelial barrier integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RASIP1 is an endothelial-enriched adaptor protein that links Ras-superfamily GTPase signaling to the control of vascular lumen formation, endothelial junction organization, and angiogenesis [#2, #7]. It functions as a direct effector of RAP1 and RAS: its RA domain forms a dimer that binds two molecules of active RAP1 (KD ~0.9 \\u03bcM) or RAS (KD ~2.2 \\u03bcM) at the GTPase Switch I region, defining it as a cooperative, membrane-associated GTPase sensor [#8], and it is recruited to nascent endothelial cell\\u2013cell contacts in an EPAC1\\u2013RAP1-dependent manner [#4]. Junctional tethering requires the transmembrane receptor HEG1, which binds a central region of RASIP1 and acts downstream of the Ccm1\\u2013Heg1 complex to localize RASIP1 to junctions; deletion of the HEG1-binding region abolishes junctional localization, ROCK inhibition, and barrier integrity [#5, #11]. At the junction RASIP1 coordinates opposing GTPase pools during tubulogenesis: it activates a CDC42\\u2013PAK4\\u2013nonmuscle myosin II module to clear apical junctions during lumen opening, and then suppresses RhoA/ROCK/myosin II contractility through its partner ARHGAP29 to permit controlled vessel expansion and maintain barrier function [#3, #6]. This activity is required for blood and lymphatic vessel lumenogenesis, tricellular and apical junction stability, and angiogenic sprouting, while being dispensable for established quiescent vessels [#2, #7, #9, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that RASIP1 is a GTP-dependent Ras effector, answering whether it physically and functionally couples to active Ras.\",\n      \"evidence\": \"Co-IP, in vitro binding requiring an intact Ras effector domain, juxta-Golgi localization, and synergistic NIH3T3 transformation with activated Raf\",\n      \"pmids\": [\"15031288\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Did not connect Ras binding to a vascular function\",\n        \"Endomembrane localization not reconciled with later junctional localization\",\n        \"No structural basis for the interaction\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that RASIP1 is required for vessel formation, defining an endothelial-specific developmental role beyond cultured-cell transformation.\",\n      \"evidence\": \"siRNA knockdown in cultured endothelial cells and morpholino knockdown in Xenopus embryos\",\n      \"pmids\": [\"19272373\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular mechanism of the vascular requirement undefined\",\n        \"GTPase effector linkage to the phenotype not established\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the core mechanism: RASIP1 controls vascular lumen formation by partnering with the RhoGAP ARHGAP29 to suppress RhoA/ROCK/myosin II and promote Cdc42/Rac1.\",\n      \"evidence\": \"Rasip1 knockout mice, EC siRNA depletion, in vitro lumen assays, RhoA/Cdc42/Rac1 activity assays, Par3 localization\",\n      \"pmids\": [\"21396893\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Upstream GTPase activating RASIP1 not identified\",\n        \"Mechanism recruiting RASIP1 to membranes/junctions unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified RAP1 as the activating GTPase and placed RASIP1 within the EPAC1\\u2013RAP1 pathway controlling endothelial junctions and barrier function.\",\n      \"evidence\": \"FRET interaction with active Rap1, endogenous Co-IP, EPAC1-RAP1 junction-formation model, barrier permeability and Rho activity assays, zebrafish/mouse analysis\",\n      \"pmids\": [\"23798437\", \"23886837\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"How RAP1 binding translates to ARHGAP29 regulation mechanistically unclear\",\n        \"Structural basis of Rap1 recognition not resolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the junctional recruitment mechanism and the stepwise GTPase logic, showing HEG1 tethers RASIP1 to junctions and RASIP1 sequentially drives CDC42-PAK4-NMII then ARHGAP29-mediated RhoA suppression.\",\n      \"evidence\": \"HEG1 proteomic screen, direct binding and mitochondrial relocalization, deletion mutagenesis, conditional Rasip1/Cdc42 knockouts, Pak4/NMII pharmacology, ROCK and junction assays\",\n      \"pmids\": [\"26780829\", \"27486147\", \"26897025\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"How a single adaptor temporally switches between opposing GTPase pools is not fully resolved\",\n        \"Requirement is context-dependent (angiogenesis vs quiescent vessels) by unknown determinants\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis for RASIP1 acting as a cooperative GTPase sensor, showing its RA domain dimerizes to bind two RAP1 or RAS molecules at Switch I.\",\n      \"evidence\": \"X-ray crystallography of the RRA domain alone and with Rap1 at 2.8 \\u00c5, with quantitative affinity measurements (Rap1 KD 0.9 \\u03bcM, Ras KD 2.2 \\u03bcM)\",\n      \"pmids\": [\"27839947\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Functional consequence of cooperative dimeric binding in cells not directly tested\",\n        \"Selectivity between Rap1 and Ras in vivo not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended RASIP1 function to the lymphatic system and confirmed CDC42 as a key downstream effector via genetic rescue.\",\n      \"evidence\": \"Lymphatic EC-specific conditional knockout, junction/cytoskeleton assays, Cdc42 activity assay, Cdc42 rescue of the deficient phenotype\",\n      \"pmids\": [\"30042182\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Whether lymphatic and blood vessel mechanisms are identical not established\",\n        \"Role in valve formation mechanistically undefined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed transcriptional and growth-factor control of RASIP1 and a role in cancer cell migration, broadening its context beyond vascular development.\",\n      \"evidence\": \"ChIP and luciferase reporter showing RUNX1 binds the Rasip1 promoter, siRNA, migration assays, Rac1 activity, EGFR-dependent expression/localization in NSCLC cells\",\n      \"pmids\": [\"30349386\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Generality of RUNX1/EGFR regulation across cell types unknown\",\n        \"Single-lab cancer migration link not independently confirmed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined RASIP1's role in junction subcellular architecture and confirmed its dependence on the Ccm1\\u2013Heg1 complex for junctional localization.\",\n      \"evidence\": \"Zebrafish rasip1 mutants with live imaging of F-actin/junctions and epistasis with ccm1 and heg1\",\n      \"pmids\": [\"34383884\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular steps linking junctional tethering to apical compartment stability unresolved\",\n        \"Role of Ccm1 in the HEG1-RASIP1 binding interaction not biochemically defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RASIP1 temporally and spatially coordinates the switch between CDC42-driven junction clearance and ARHGAP29-mediated RhoA suppression at the molecular level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No mechanism explaining how one adaptor sequentially activates opposing GTPase modules\",\n        \"Structural basis for ARHGAP29 binding and regulation not determined\",\n        \"Determinants of context-dependent requirement (angiogenic vs quiescent) unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 5, 11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 7, 9]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAP1\", \"RAS\", \"ARHGAP29\", \"HEG1\", \"CDC42\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}