{"gene":"MYRIP","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2002,"finding":"MYRIP (MyRIP) was identified as a novel protein that binds to myosin VIIa and to Rab27A in a GTP-dependent manner. In retinal pigment epithelium cells, MyRIP, myosin VIIa, and Rab27A co-associate with melanosomes, and overexpression of MyRIP interferes with myosin VIIa tail localization in transfected PC12 cells, indicating MyRIP bridges melanosomes to the actin cytoskeleton via this complex.","method":"Co-immunoprecipitation, GTP-dependent binding assay, overexpression in PC12 cells, immunolocalization in RPE cells","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and cell-based localization with functional overexpression readout, single lab, two orthogonal methods","pmids":["11964381"],"is_preprint":false},{"year":2002,"finding":"Slac2-c/MYRIP was identified as a linker protein with an N-terminal Slp homology domain (SHD) that binds GTP-bound Rab27A/B both in vitro and in intact cells, a middle region that binds myosin Va and myosin VIIa, and a C-terminal actin-binding domain. The actin-binding domain colocalizes with actin filaments at the cell periphery when expressed in PC12 cells and melanoma cells.","method":"In vitro binding assays, GST pulldown, co-immunoprecipitation, immunofluorescence in transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding reconstitution with multiple orthogonal methods (pulldown, co-IP, cell imaging), independently corroborated by multiple labs","pmids":["12221080"],"is_preprint":false},{"year":2003,"finding":"Slac2c/MyRIP is associated with insulin-containing secretory granules of pancreatic beta-cells. siRNA knockdown of Slac2c/MyRIP severely impairs hormone release in response to secretagogues. Overexpression of the actin-binding domain (but not the myosin Va-binding domain) of Slac2c/MyRIP potently inhibits exocytosis, and point mutations abolishing actin binding prevent this inhibition, demonstrating that the actin-binding domain is the key functional element for regulating insulin exocytosis.","method":"siRNA knockdown, overexpression of domain mutants, insulin secretion assay, point mutagenesis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean siRNA KD with secretion readout plus domain mutagenesis identifying specific functional domain, multiple orthogonal approaches in single study","pmids":["14517322"],"is_preprint":false},{"year":2005,"finding":"In vitro binding experiments showed that myosin VIIa has greater affinity for Slac2-c/MYRIP than myosin Va, and the myosin VIIa-binding domain is distinct from the myosin Va-binding domain. In melanocytes, ectopic expression of Slac2-c recruits co-expressed myosin VIIa to melanosomes via Rab27A interaction, and the Slac2-c/myosin VIIa complex rescues normal melanosome distribution in Slac2-a-depleted melanocytes, establishing Slac2-c as a functional myosin VIIa receptor.","method":"In vitro pulldown, co-immunoprecipitation, siRNA knockdown of Slac2-a, ectopic expression with fluorescent tags in melanocytes, melanosome distribution assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding + mutagenesis + reconstitution in cells with genetic rescue, multiple orthogonal methods in one study","pmids":["15927964"],"is_preprint":false},{"year":2007,"finding":"MYRIP was identified as a member of the AKAP (A-kinase anchoring protein) family. Mouse MyRIP targets the type II PKA holoenzyme to a specific perinuclear region of insulin-secreting cells via an atypical mechanism. MyRIP also interacts with the Sec6 and Sec8 components of the exocyst complex, linking PKA to the exocytosis machinery.","method":"Yeast two-hybrid screen (zebrafish ortholog Ze-AKAP2), biochemical pulldown, co-immunoprecipitation, immunofluorescence in insulin-secreting cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and cell imaging, single lab, two orthogonal methods","pmids":["17827149"],"is_preprint":false},{"year":2007,"finding":"All three proteins Rab27a, Myrip, and Myosin VIIa co-immunoprecipitate in heterologous cultured cells and co-localize at the peripheral membrane of RPE melanosomes. Live-cell imaging of RPE primary cultures shows that loss of any one of the three components (ashen/Rab27a-deficient, shaker-1/MyoVIIa mutant, or Myrip-knockdown cells) leads to increased melanosome motility with more frequent fast movements and inversion of directionality, similar to cytochalasin D treatment, indicating the Rab27a-Myrip-MyoVIIa complex tethers melanosomes to actin filaments for peripheral directionality.","method":"Co-immunoprecipitation, immunofluorescence and immunoelectron microscopy, live-cell imaging of RPE primary cultures, adenoviral knockdown, mutant mouse RPE cells, cytochalasin D treatment","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, live-cell imaging with multiple genetic knockouts/knockdowns, cytoskeletal drug validation, multiple orthogonal methods across labs","pmids":["17451552"],"is_preprint":false},{"year":2007,"finding":"In RPE cells, MYRIP is linked to melanosomes via RAB27A as shown by mutant mouse analysis, but recruitment of MYRIP to the apical RPE region is independent of melanosomes and RAB27A. RAB27A provides an essential link to melanosomes, and RAB27A together with MYRIP also associates with motile small vesicles of unknown origin.","method":"RPE primary cultures, live-cell imaging, mutant mouse retina analysis, cell fractionation","journal":"Cell motility and the cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse models plus live-cell imaging and fractionation, single lab","pmids":["17352418"],"is_preprint":false},{"year":2009,"finding":"Rab27a and MyRIP are present on mature Weibel-Palade bodies (WPBs) in endothelial cells and anchor WPBs to peripheral actin. siRNA depletion of either Rab27a or MyRIP causes loss of peripheral WPB localization, increases both basal and stimulated secretion, and results in VWF that is less multimerized with shorter platelet-binding strings under flow.","method":"siRNA depletion in primary endothelial cells, immunofluorescence localization, VWF secretion assay, VWF multimerization analysis, flow-based string assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA with multiple functional readouts (localization, secretion, multimerization, string formation), reciprocal Rab/effector knockdown comparison","pmids":["19270261"],"is_preprint":false},{"year":2009,"finding":"Myrip recruits and activates myosin Va on skin melanosomes with similar efficiency to melanophilin. Mutagenesis demonstrated that a conserved Myrip-Melanophilin amphipathic helix (MMAH) is essential for myosin Va interaction, while Myrip-specific inserts (not the MMAH) are essential for myosin VIIa activation, showing that Myrip activates MyoVa and MyoVIIa via non-overlapping distinct domains.","method":"Melanocyte and RPE cell melanosome transport assays, domain mutagenesis, fluorescence microscopy","journal":"Pigment cell & melanoma research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with functional cell-based readout, single lab, two cell-type systems","pmids":["19317802"],"is_preprint":false},{"year":2009,"finding":"After beta-adrenergic stimulation of rat parotid acinar cells, Slac2-c/MYRIP is rapidly recruited from secretory granules to the apical plasma membrane fraction and subsequently translocated to the cytosol. In the cytosolic fraction, Slac2-c is Ca2+-dependently proteolyzed, likely via PEST sequences, indicating dynamic redistribution and degradation after exocytosis.","method":"Subcellular fractionation, isoproterenol stimulation, Ca2+ treatment, immunoblotting","journal":"Archives of oral biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — fractionation with pharmacological stimulation, functional implication of redistribution, single lab","pmids":["19185850"],"is_preprint":false},{"year":2011,"finding":"Myosin Va forms a tripartite complex with Rab27a and MyRIP on Weibel-Palade bodies in endothelial cells. Depletion of or dominant-negative interference with myosin Va increases the ratio of perinuclear to peripheral WPBs and elevates secretion of less-oligomeric VWF from histamine-stimulated cells, indicating the Rab27a/MyRIP/myosin Va complex links WPBs to peripheral actin for maturation.","method":"Co-immunoprecipitation, siRNA depletion, dominant-negative overexpression, immunofluorescence, VWF oligomerization analysis","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus siRNA with functional readout, single lab","pmids":["21740491"],"is_preprint":false},{"year":2012,"finding":"MYRIP acts as a negative regulator of WPB exocytosis and Slp4-a acts as a positive regulator; both effects are mediated by Rab27A. siRNA knockdown and overexpression experiments show that the balance of Rab27A fractional occupancy by Slp4-a vs. MyRIP on WPBs determines the probability of WPB exocytosis.","method":"siRNA knockdown, EGFP-tagged overexpression, live-cell imaging, exocytosis quantification in endothelial cells","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and overexpression with functional exocytosis readout, single lab, two complementary perturbations","pmids":["22898601"],"is_preprint":false},{"year":2012,"finding":"In human enterochromaffin cells, Myrip (1) inhibits fast directed secretory granule movement (facilitating dissociation from microtubules), (2) enhances granule motion toward and attachment to the plasma membrane, and (3) increases granule immobilization time at the plasma membrane. Effects (1) and (2) depend on myosin Va recruitment, while effect (3) is myosin Va-independent but requires the C-terminal domain of Myrip, likely involving actin/exocyst interactions.","method":"TIRF microscopy, single-particle tracking, photoconversion assay, mathematical modeling, domain deletion/mutation analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal quantitative imaging methods plus domain mutagenesis, domain-specific functional dissection in single rigorous study","pmids":["22396429"],"is_preprint":false},{"year":2012,"finding":"In glucose-stimulated pancreatic beta cells, MyRIP does not interact with the brain isoform of myosin Va (BR-MyoVa) under basal conditions. However, elevation of cAMP by incretin hormones leads to MyRIP phosphorylation, its interaction with BR-MyoVa, and phosphorylation of the secretory granule-associated protein rabphilin-3A (Rph-3A) on Ser-234. siRNA knockdown of MyRIP reduces cAMP-mediated Rph-3A phosphorylation and hormone secretion, and phosphomutant/phosphomimic Rph-3A significantly alters hormone release when PKA is activated.","method":"In vitro pulldown, co-immunoprecipitation, siRNA knockdown, phosphorylation assay, phosphomutant expression, insulin secretion assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus siRNA plus mutagenesis in single study, single lab, multiple orthogonal methods","pmids":["22993210"],"is_preprint":false},{"year":2015,"finding":"In endothelial cells, MyRIP restricts WPB movement through its actin-binding domain rather than through its myosin Va-binding domain. For Ca2+-driven exocytosis, both MyoVa- and actin-binding are required, but actin-binding plays the dominant role. These conclusions were established using EGFP-MyRIP point mutants with disrupted MyoVa and/or actin binding and high-speed live-cell fluorescence microscopy.","method":"Point mutagenesis of MyRIP (disrupting MyoVa- and/or actin-binding), high-speed live-cell fluorescence microscopy, actin disruption/stabilization experiments, Ca2+-evoked exocytosis assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with multiple orthogonal functional readouts (motility and exocytosis), pharmacological validation, rigorous domain dissection","pmids":["26675235"],"is_preprint":false},{"year":2017,"finding":"Exophilin-8/MYRIP accumulates secretory granules in the cortical F-actin network not by direct interaction with myosin Va, but through indirect interaction with myosin VIIa via a previously unknown binding partner, RIM-BP2. RIM-BP2 also associates with exocytic machinery components Cav1.3, RIM, and Munc13-1. Ablation or knockdown of exophilin-8, RIM-BP2, or myosin VIIa markedly decreases both peripheral granule accumulation and exocytosis. In exophilin-8-null mouse pancreatic islets, polarized granule localization is lost and insulin secretion is impaired.","method":"Co-immunoprecipitation, knockdown/knockout mouse models, immunofluorescence, insulin secretion assay, interaction domain mapping","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse plus multiple knockdowns plus co-IP identifying new binding partner, multiple orthogonal methods with functional validation","pmids":["28673385"],"is_preprint":false}],"current_model":"MYRIP/Slac2-c is a scaffolding/adaptor protein that links Rab27A-positive secretory organelles (melanosomes, secretory granules, Weibel-Palade bodies) to the actin cytoskeleton and exocytic machinery: its N-terminal SHD binds GTP-Rab27A, its middle region activates myosin Va (via a conserved amphipathic helix) and myosin VIIa (via distinct Myrip-specific inserts), and its C-terminal domain directly binds F-actin; additionally, MYRIP serves as an AKAP that recruits PKA to secretory organelles via an atypical mechanism and interacts with the exocyst (Sec6/Sec8) and, via RIM-BP2, with the active zone-like machinery (Cav1.3, RIM, Munc13-1), thereby coupling organelle capture in the cortical actin network, transport to the plasma membrane, tethering, and exocytosis in a cAMP/PKA-regulated manner."},"narrative":{"mechanistic_narrative":"MYRIP (Slac2-c) is a multidomain Rab27A effector that tethers secretory organelles to the cortical actin cytoskeleton and couples their capture, transport, and exocytosis [PMID:12221080, PMID:15927964]. Its N-terminal Slp homology domain binds GTP-loaded Rab27A/B, a middle region engages the unconventional myosins Va and VIIa through non-overlapping interfaces, and a C-terminal domain binds F-actin directly [PMID:12221080, PMID:19317802]. This modular architecture is deployed on Rab27A-positive organelles across cell types: melanosomes in retinal pigment epithelium and melanocytes, where the Rab27A–MYRIP–myosin VIIa complex anchors organelles to peripheral actin to control distribution and motility [PMID:11964381, PMID:15927964, PMID:17451552]; insulin granules in pancreatic beta cells, where MYRIP is required for stimulated hormone release [PMID:14517322, PMID:28673385]; and Weibel-Palade bodies in endothelial cells, where it anchors organelles to peripheral actin and influences von Willebrand factor multimerization and secretion [PMID:19270261, PMID:21740491]. Domain-dissection studies establish the actin-binding domain as the dominant functional element restricting organelle motility and gating exocytosis, with myosin binding playing a secondary role [PMID:14517322, PMID:26675235]. MYRIP acts at multiple steps of granule trafficking — inhibiting fast directed movement, enhancing attachment to the plasma membrane, and prolonging immobilization there — with the early steps requiring myosin Va and the immobilization step requiring the C-terminal/actin-exocyst module [PMID:22396429]. Beyond actin and myosin coupling, MYRIP is an A-kinase anchoring protein that targets type II PKA to secretory organelles and links to the exocyst via Sec6/Sec8 [PMID:17827149], and incretin/cAMP signaling drives MYRIP phosphorylation, its inducible interaction with myosin Va, and downstream phosphorylation of rabphilin-3A to regulate secretion [PMID:22993210]. At the active-zone-like tethering machinery, MYRIP recruits granules to cortical actin via myosin VIIa indirectly through RIM-BP2, which associates with Cav1.3, RIM, and Munc13-1 [PMID:28673385]. Its function in exocytosis is bidirectionally tunable: MYRIP behaves as a negative regulator of Weibel-Palade body exocytosis whose effect is set by Rab27A fractional occupancy relative to the positive regulator Slp4-a [PMID:22898601].","teleology":[{"year":2002,"claim":"Established MYRIP's foundational identity as a bridge linking Rab27A-positive melanosomes to the actin cytoskeleton, answering how organelle-bound Rab27A connects to motor and cytoskeletal machinery.","evidence":"Co-IP and GTP-dependent binding assays with overexpression and immunolocalization in RPE and PC12 cells","pmids":["11964381","12221080"],"confidence":"High","gaps":["Domain boundaries defined biochemically but functional necessity in vivo not yet tested","Whether myosin Va versus VIIa preference matters functionally unresolved at this stage"]},{"year":2003,"claim":"Defined which MYRIP domain drives function in regulated exocytosis, showing the actin-binding domain — not the myosin Va-binding domain — is the key element controlling insulin secretion.","evidence":"siRNA knockdown, domain-mutant overexpression, and point mutagenesis with insulin secretion assays in beta cells","pmids":["14517322"],"confidence":"High","gaps":["Mechanism by which actin binding restrains versus promotes secretion not resolved","Did not address myosin VIIa or PKA contributions"]},{"year":2005,"claim":"Distinguished MYRIP as a functional myosin VIIa receptor with higher affinity than for myosin Va, clarifying motor specificity on melanosomes.","evidence":"In vitro pulldown, co-IP, Slac2-a depletion with rescue, and melanosome distribution assays in melanocytes","pmids":["15927964"],"confidence":"High","gaps":["Relative in vivo usage of myosin Va vs VIIa across cell types not established","Mechanism of motor activation not yet mapped"]},{"year":2007,"claim":"Demonstrated the Rab27a-MYRIP-myosin VIIa tripartite complex tethers melanosomes to actin to control directionality, and that MYRIP also functions as an AKAP linking PKA to the exocyst.","evidence":"Live-cell imaging of mutant/knockdown RPE cells with cytochalasin D; yeast two-hybrid, pulldown, co-IP in insulin-secreting cells","pmids":["17451552","17827149","17352418"],"confidence":"High","gaps":["Atypical PKA-anchoring mechanism not structurally defined","How AKAP and actin-tethering functions are coordinated unknown","Identity of MYRIP-associated motile small vesicles unresolved"]},{"year":2009,"claim":"Extended MYRIP's tethering role to endothelial Weibel-Palade bodies and dissected how distinct domains activate myosin Va versus myosin VIIa, while revealing dynamic stimulus-driven redistribution and proteolysis.","evidence":"siRNA in endothelial cells with VWF secretion/multimerization assays; domain mutagenesis in melanocyte transport assays; subcellular fractionation after beta-adrenergic stimulation","pmids":["19270261","19317802","19185850"],"confidence":"High","gaps":["MMAH vs Myrip-specific insert structural basis of motor selectivity not solved","Protease and PEST-dependent degradation pathway not identified molecularly"]},{"year":2011,"claim":"Confirmed a Rab27a/MYRIP/myosin Va tripartite complex on Weibel-Palade bodies governs peripheral positioning and VWF oligomerization quality.","evidence":"Co-IP, siRNA, dominant-negative myosin Va, and VWF oligomerization analysis in endothelial cells","pmids":["21740491"],"confidence":"Medium","gaps":["Single-lab co-IP; reciprocal validation across systems limited","How peripheral positioning mechanistically improves VWF maturation unclear"]},{"year":2012,"claim":"Resolved MYRIP as a multi-step regulator of granule trafficking with separable myosin Va-dependent and actin/exocyst-dependent functions, and showed its exocytosis output is bidirectionally tunable via Rab27A occupancy and cAMP/PKA signaling.","evidence":"TIRF single-particle tracking with domain mutants in enterochromaffin cells; siRNA/overexpression live-cell exocytosis in endothelial cells; cAMP-driven phosphorylation, co-IP, phosphomutant secretion assays in beta cells","pmids":["22396429","22898601","22993210"],"confidence":"High","gaps":["Kinase(s) directly phosphorylating MYRIP not pinpointed","How Slp4-a/MYRIP competition is regulated physiologically unknown"]},{"year":2015,"claim":"Quantitatively established the actin-binding domain as dominant over the myosin Va-binding domain for both restricting organelle motility and supporting Ca2+-driven exocytosis.","evidence":"MYRIP point mutants disrupting MyoVa and/or actin binding with high-speed live-cell microscopy and actin perturbation in endothelial cells","pmids":["26675235"],"confidence":"High","gaps":["Molecular nature of the actin-dependent exocytosis step not defined","Generalizability beyond Weibel-Palade bodies not tested here"]},{"year":2017,"claim":"Identified RIM-BP2 as the previously unknown adaptor through which MYRIP/exophilin-8 engages myosin VIIa and active-zone-like exocytic machinery, mechanistically linking cortical actin capture to docking and exocytosis.","evidence":"Co-IP with interaction mapping, knockdown and knockout mouse islets, immunofluorescence, and insulin secretion assays","pmids":["28673385"],"confidence":"High","gaps":["Structural basis of the MYRIP-RIM-BP2-myosin VIIa interaction unresolved","How this complex integrates with the AKAP/PKA module not addressed"]},{"year":null,"claim":"How MYRIP's multiple coupled functions — Rab27A tethering, dual myosin activation, actin binding, PKA anchoring, and RIM-BP2-mediated docking — are spatiotemporally integrated to switch organelle capture into productive exocytosis remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length MYRIP with its partners","Direct kinase responsible for cAMP-driven MYRIP phosphorylation unidentified","Mechanism setting the negative-vs-positive regulatory balance at single organelles not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,15]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,11]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,7,12]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,5,14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,7,12,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,13]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[7,10]}],"complexes":["Rab27A-MYRIP-myosin VIIa complex","Rab27a-MYRIP-myosin Va complex","exocyst (Sec6/Sec8)"],"partners":["RAB27A","MYO7A","MYO5A","RIMBP2","EXOC3","EXOC4","PRKAR2","RPH3A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NFW9","full_name":"Rab effector MyRIP","aliases":["Exophilin-8","Myosin-VIIa- and Rab-interacting protein","Synaptotagmin-like protein lacking C2 domains C","SlaC2-c","Slp homolog lacking C2 domains c"],"length_aa":859,"mass_kda":95.7,"function":"Rab effector protein involved in melanosome transport. Serves as link between melanosome-bound RAB27A and the motor proteins MYO5A and MYO7A. May link RAB27A-containing vesicles to actin filaments. Functions as a protein kinase A-anchoring protein (AKAP). May act as a scaffolding protein that links PKA to components of the exocytosis machinery, thus facilitating exocytosis, including insulin release (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Cytoplasmic vesicle, secretory vesicle","url":"https://www.uniprot.org/uniprotkb/Q8NFW9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYRIP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYRIP","total_profiled":1310},"omim":[{"mim_id":"611790","title":"MYOSIN VIIA- AND RAB-INTERACTING PROTEIN; MYRIP","url":"https://www.omim.org/entry/611790"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":34.9}],"url":"https://www.proteinatlas.org/search/MYRIP"},"hgnc":{"alias_symbol":["DKFZp586F1018","exophilin-8","SLAC2-C","SLAC2C"],"prev_symbol":[]},"alphafold":{"accession":"Q8NFW9","domains":[{"cath_id":"3.30.40.10","chopping":"11-129","consensus_level":"medium","plddt":92.7129,"start":11,"end":129}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFW9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFW9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFW9-F1-predicted_aligned_error_v6.png","plddt_mean":57.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYRIP","jax_strain_url":"https://www.jax.org/strain/search?query=MYRIP"},"sequence":{"accession":"Q8NFW9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFW9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFW9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFW9"}},"corpus_meta":[{"pmid":"11964381","id":"PMC_11964381","title":"MyRIP, a novel Rab effector, enables myosin VIIa recruitment to retinal melanosomes.","date":"2002","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/11964381","citation_count":148,"is_preprint":false},{"pmid":"12221080","id":"PMC_12221080","title":"Slac2-c (synaptotagmin-like protein homologue lacking C2 domains-c), a novel linker protein that interacts with Rab27, myosin Va/VIIa, and actin.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12221080","citation_count":137,"is_preprint":false},{"pmid":"14517322","id":"PMC_14517322","title":"Involvement of the Rab27 binding protein Slac2c/MyRIP in insulin exocytosis.","date":"2003","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/14517322","citation_count":135,"is_preprint":false},{"pmid":"19270261","id":"PMC_19270261","title":"Rab27a and MyRIP regulate the amount and multimeric state of VWF released from endothelial cells.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19270261","citation_count":88,"is_preprint":false},{"pmid":"22898601","id":"PMC_22898601","title":"The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22898601","citation_count":83,"is_preprint":false},{"pmid":"17451552","id":"PMC_17451552","title":"The ternary Rab27a-Myrip-Myosin VIIa complex regulates melanosome motility in the retinal pigment epithelium.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/17451552","citation_count":79,"is_preprint":false},{"pmid":"21740491","id":"PMC_21740491","title":"Myosin Va acts in concert with Rab27a and MyRIP to regulate acute von-Willebrand factor release from endothelial cells.","date":"2011","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/21740491","citation_count":64,"is_preprint":false},{"pmid":"20861866","id":"PMC_20861866","title":"Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration.","date":"2010","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20861866","citation_count":52,"is_preprint":false},{"pmid":"17827149","id":"PMC_17827149","title":"MyRIP anchors protein kinase A to the exocyst complex.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17827149","citation_count":38,"is_preprint":false},{"pmid":"15927964","id":"PMC_15927964","title":"Functional analysis of Slac2-c/MyRIP as a linker protein between melanosomes and myosin VIIa.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15927964","citation_count":35,"is_preprint":false},{"pmid":"26675235","id":"PMC_26675235","title":"Interaction between MyRIP and the actin cytoskeleton regulates Weibel-Palade body trafficking and exocytosis.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/26675235","citation_count":32,"is_preprint":false},{"pmid":"16473609","id":"PMC_16473609","title":"Identification and biochemical analysis of Slac2-c/MyRIP as a Rab27A-, myosin Va/VIIa-, and actin-binding protein.","date":"2005","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/16473609","citation_count":32,"is_preprint":false},{"pmid":"17352418","id":"PMC_17352418","title":"Analysis of the linkage of MYRIP and MYO7A to melanosomes by RAB27A in retinal pigment epithelial cells.","date":"2007","source":"Cell motility and the cytoskeleton","url":"https://pubmed.ncbi.nlm.nih.gov/17352418","citation_count":29,"is_preprint":false},{"pmid":"22396429","id":"PMC_22396429","title":"Myrip couples the capture of secretory granules by the actin-rich cell cortex and their attachment to the plasma membrane.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22396429","citation_count":24,"is_preprint":false},{"pmid":"28673385","id":"PMC_28673385","title":"Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28673385","citation_count":19,"is_preprint":false},{"pmid":"19317802","id":"PMC_19317802","title":"Myrip uses distinct domains in the cellular activation of myosin VA and myosin VIIA in melanosome transport.","date":"2009","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/19317802","citation_count":19,"is_preprint":false},{"pmid":"22993210","id":"PMC_22993210","title":"MyRIP interaction with MyoVa on secretory granules is controlled by the cAMP-PKA pathway.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22993210","citation_count":18,"is_preprint":false},{"pmid":"19185850","id":"PMC_19185850","title":"Redistribution of Rab27-specific effector Slac2-c, but not Slp4-a, after isoproterenol-stimulation in rat parotid acinar cells.","date":"2009","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/19185850","citation_count":8,"is_preprint":false},{"pmid":"33679876","id":"PMC_33679876","title":"Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify MYRIP, TRAPPC11, and SLC27A6 of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33679876","citation_count":6,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.18.638894","title":"A Genetic Analysis of Lipid Metabolism Regulation in Han Chinese Youth in Xinjiang via Extreme Phenotypic Strategies","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.18.638894","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12170,"output_tokens":4611,"usd":0.052838,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12573,"output_tokens":3947,"usd":0.08077,"stage2_stop_reason":"end_turn"},"total_usd":0.133608,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"MYRIP (MyRIP) was identified as a novel protein that binds to myosin VIIa and to Rab27A in a GTP-dependent manner. In retinal pigment epithelium cells, MyRIP, myosin VIIa, and Rab27A co-associate with melanosomes, and overexpression of MyRIP interferes with myosin VIIa tail localization in transfected PC12 cells, indicating MyRIP bridges melanosomes to the actin cytoskeleton via this complex.\",\n      \"method\": \"Co-immunoprecipitation, GTP-dependent binding assay, overexpression in PC12 cells, immunolocalization in RPE cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and cell-based localization with functional overexpression readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"11964381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Slac2-c/MYRIP was identified as a linker protein with an N-terminal Slp homology domain (SHD) that binds GTP-bound Rab27A/B both in vitro and in intact cells, a middle region that binds myosin Va and myosin VIIa, and a C-terminal actin-binding domain. The actin-binding domain colocalizes with actin filaments at the cell periphery when expressed in PC12 cells and melanoma cells.\",\n      \"method\": \"In vitro binding assays, GST pulldown, co-immunoprecipitation, immunofluorescence in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding reconstitution with multiple orthogonal methods (pulldown, co-IP, cell imaging), independently corroborated by multiple labs\",\n      \"pmids\": [\"12221080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Slac2c/MyRIP is associated with insulin-containing secretory granules of pancreatic beta-cells. siRNA knockdown of Slac2c/MyRIP severely impairs hormone release in response to secretagogues. Overexpression of the actin-binding domain (but not the myosin Va-binding domain) of Slac2c/MyRIP potently inhibits exocytosis, and point mutations abolishing actin binding prevent this inhibition, demonstrating that the actin-binding domain is the key functional element for regulating insulin exocytosis.\",\n      \"method\": \"siRNA knockdown, overexpression of domain mutants, insulin secretion assay, point mutagenesis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean siRNA KD with secretion readout plus domain mutagenesis identifying specific functional domain, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"14517322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In vitro binding experiments showed that myosin VIIa has greater affinity for Slac2-c/MYRIP than myosin Va, and the myosin VIIa-binding domain is distinct from the myosin Va-binding domain. In melanocytes, ectopic expression of Slac2-c recruits co-expressed myosin VIIa to melanosomes via Rab27A interaction, and the Slac2-c/myosin VIIa complex rescues normal melanosome distribution in Slac2-a-depleted melanocytes, establishing Slac2-c as a functional myosin VIIa receptor.\",\n      \"method\": \"In vitro pulldown, co-immunoprecipitation, siRNA knockdown of Slac2-a, ectopic expression with fluorescent tags in melanocytes, melanosome distribution assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding + mutagenesis + reconstitution in cells with genetic rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15927964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MYRIP was identified as a member of the AKAP (A-kinase anchoring protein) family. Mouse MyRIP targets the type II PKA holoenzyme to a specific perinuclear region of insulin-secreting cells via an atypical mechanism. MyRIP also interacts with the Sec6 and Sec8 components of the exocyst complex, linking PKA to the exocytosis machinery.\",\n      \"method\": \"Yeast two-hybrid screen (zebrafish ortholog Ze-AKAP2), biochemical pulldown, co-immunoprecipitation, immunofluorescence in insulin-secreting cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and cell imaging, single lab, two orthogonal methods\",\n      \"pmids\": [\"17827149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"All three proteins Rab27a, Myrip, and Myosin VIIa co-immunoprecipitate in heterologous cultured cells and co-localize at the peripheral membrane of RPE melanosomes. Live-cell imaging of RPE primary cultures shows that loss of any one of the three components (ashen/Rab27a-deficient, shaker-1/MyoVIIa mutant, or Myrip-knockdown cells) leads to increased melanosome motility with more frequent fast movements and inversion of directionality, similar to cytochalasin D treatment, indicating the Rab27a-Myrip-MyoVIIa complex tethers melanosomes to actin filaments for peripheral directionality.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence and immunoelectron microscopy, live-cell imaging of RPE primary cultures, adenoviral knockdown, mutant mouse RPE cells, cytochalasin D treatment\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, live-cell imaging with multiple genetic knockouts/knockdowns, cytoskeletal drug validation, multiple orthogonal methods across labs\",\n      \"pmids\": [\"17451552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In RPE cells, MYRIP is linked to melanosomes via RAB27A as shown by mutant mouse analysis, but recruitment of MYRIP to the apical RPE region is independent of melanosomes and RAB27A. RAB27A provides an essential link to melanosomes, and RAB27A together with MYRIP also associates with motile small vesicles of unknown origin.\",\n      \"method\": \"RPE primary cultures, live-cell imaging, mutant mouse retina analysis, cell fractionation\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse models plus live-cell imaging and fractionation, single lab\",\n      \"pmids\": [\"17352418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rab27a and MyRIP are present on mature Weibel-Palade bodies (WPBs) in endothelial cells and anchor WPBs to peripheral actin. siRNA depletion of either Rab27a or MyRIP causes loss of peripheral WPB localization, increases both basal and stimulated secretion, and results in VWF that is less multimerized with shorter platelet-binding strings under flow.\",\n      \"method\": \"siRNA depletion in primary endothelial cells, immunofluorescence localization, VWF secretion assay, VWF multimerization analysis, flow-based string assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA with multiple functional readouts (localization, secretion, multimerization, string formation), reciprocal Rab/effector knockdown comparison\",\n      \"pmids\": [\"19270261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Myrip recruits and activates myosin Va on skin melanosomes with similar efficiency to melanophilin. Mutagenesis demonstrated that a conserved Myrip-Melanophilin amphipathic helix (MMAH) is essential for myosin Va interaction, while Myrip-specific inserts (not the MMAH) are essential for myosin VIIa activation, showing that Myrip activates MyoVa and MyoVIIa via non-overlapping distinct domains.\",\n      \"method\": \"Melanocyte and RPE cell melanosome transport assays, domain mutagenesis, fluorescence microscopy\",\n      \"journal\": \"Pigment cell & melanoma research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with functional cell-based readout, single lab, two cell-type systems\",\n      \"pmids\": [\"19317802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"After beta-adrenergic stimulation of rat parotid acinar cells, Slac2-c/MYRIP is rapidly recruited from secretory granules to the apical plasma membrane fraction and subsequently translocated to the cytosol. In the cytosolic fraction, Slac2-c is Ca2+-dependently proteolyzed, likely via PEST sequences, indicating dynamic redistribution and degradation after exocytosis.\",\n      \"method\": \"Subcellular fractionation, isoproterenol stimulation, Ca2+ treatment, immunoblotting\",\n      \"journal\": \"Archives of oral biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — fractionation with pharmacological stimulation, functional implication of redistribution, single lab\",\n      \"pmids\": [\"19185850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Myosin Va forms a tripartite complex with Rab27a and MyRIP on Weibel-Palade bodies in endothelial cells. Depletion of or dominant-negative interference with myosin Va increases the ratio of perinuclear to peripheral WPBs and elevates secretion of less-oligomeric VWF from histamine-stimulated cells, indicating the Rab27a/MyRIP/myosin Va complex links WPBs to peripheral actin for maturation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, dominant-negative overexpression, immunofluorescence, VWF oligomerization analysis\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus siRNA with functional readout, single lab\",\n      \"pmids\": [\"21740491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MYRIP acts as a negative regulator of WPB exocytosis and Slp4-a acts as a positive regulator; both effects are mediated by Rab27A. siRNA knockdown and overexpression experiments show that the balance of Rab27A fractional occupancy by Slp4-a vs. MyRIP on WPBs determines the probability of WPB exocytosis.\",\n      \"method\": \"siRNA knockdown, EGFP-tagged overexpression, live-cell imaging, exocytosis quantification in endothelial cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and overexpression with functional exocytosis readout, single lab, two complementary perturbations\",\n      \"pmids\": [\"22898601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In human enterochromaffin cells, Myrip (1) inhibits fast directed secretory granule movement (facilitating dissociation from microtubules), (2) enhances granule motion toward and attachment to the plasma membrane, and (3) increases granule immobilization time at the plasma membrane. Effects (1) and (2) depend on myosin Va recruitment, while effect (3) is myosin Va-independent but requires the C-terminal domain of Myrip, likely involving actin/exocyst interactions.\",\n      \"method\": \"TIRF microscopy, single-particle tracking, photoconversion assay, mathematical modeling, domain deletion/mutation analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal quantitative imaging methods plus domain mutagenesis, domain-specific functional dissection in single rigorous study\",\n      \"pmids\": [\"22396429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In glucose-stimulated pancreatic beta cells, MyRIP does not interact with the brain isoform of myosin Va (BR-MyoVa) under basal conditions. However, elevation of cAMP by incretin hormones leads to MyRIP phosphorylation, its interaction with BR-MyoVa, and phosphorylation of the secretory granule-associated protein rabphilin-3A (Rph-3A) on Ser-234. siRNA knockdown of MyRIP reduces cAMP-mediated Rph-3A phosphorylation and hormone secretion, and phosphomutant/phosphomimic Rph-3A significantly alters hormone release when PKA is activated.\",\n      \"method\": \"In vitro pulldown, co-immunoprecipitation, siRNA knockdown, phosphorylation assay, phosphomutant expression, insulin secretion assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus siRNA plus mutagenesis in single study, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22993210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In endothelial cells, MyRIP restricts WPB movement through its actin-binding domain rather than through its myosin Va-binding domain. For Ca2+-driven exocytosis, both MyoVa- and actin-binding are required, but actin-binding plays the dominant role. These conclusions were established using EGFP-MyRIP point mutants with disrupted MyoVa and/or actin binding and high-speed live-cell fluorescence microscopy.\",\n      \"method\": \"Point mutagenesis of MyRIP (disrupting MyoVa- and/or actin-binding), high-speed live-cell fluorescence microscopy, actin disruption/stabilization experiments, Ca2+-evoked exocytosis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with multiple orthogonal functional readouts (motility and exocytosis), pharmacological validation, rigorous domain dissection\",\n      \"pmids\": [\"26675235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Exophilin-8/MYRIP accumulates secretory granules in the cortical F-actin network not by direct interaction with myosin Va, but through indirect interaction with myosin VIIa via a previously unknown binding partner, RIM-BP2. RIM-BP2 also associates with exocytic machinery components Cav1.3, RIM, and Munc13-1. Ablation or knockdown of exophilin-8, RIM-BP2, or myosin VIIa markedly decreases both peripheral granule accumulation and exocytosis. In exophilin-8-null mouse pancreatic islets, polarized granule localization is lost and insulin secretion is impaired.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/knockout mouse models, immunofluorescence, insulin secretion assay, interaction domain mapping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse plus multiple knockdowns plus co-IP identifying new binding partner, multiple orthogonal methods with functional validation\",\n      \"pmids\": [\"28673385\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYRIP/Slac2-c is a scaffolding/adaptor protein that links Rab27A-positive secretory organelles (melanosomes, secretory granules, Weibel-Palade bodies) to the actin cytoskeleton and exocytic machinery: its N-terminal SHD binds GTP-Rab27A, its middle region activates myosin Va (via a conserved amphipathic helix) and myosin VIIa (via distinct Myrip-specific inserts), and its C-terminal domain directly binds F-actin; additionally, MYRIP serves as an AKAP that recruits PKA to secretory organelles via an atypical mechanism and interacts with the exocyst (Sec6/Sec8) and, via RIM-BP2, with the active zone-like machinery (Cav1.3, RIM, Munc13-1), thereby coupling organelle capture in the cortical actin network, transport to the plasma membrane, tethering, and exocytosis in a cAMP/PKA-regulated manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYRIP (Slac2-c) is a multidomain Rab27A effector that tethers secretory organelles to the cortical actin cytoskeleton and couples their capture, transport, and exocytosis [#1, #3]. Its N-terminal Slp homology domain binds GTP-loaded Rab27A/B, a middle region engages the unconventional myosins Va and VIIa through non-overlapping interfaces, and a C-terminal domain binds F-actin directly [#1, #8]. This modular architecture is deployed on Rab27A-positive organelles across cell types: melanosomes in retinal pigment epithelium and melanocytes, where the Rab27A–MYRIP–myosin VIIa complex anchors organelles to peripheral actin to control distribution and motility [#0, #3, #5]; insulin granules in pancreatic beta cells, where MYRIP is required for stimulated hormone release [#2, #15]; and Weibel-Palade bodies in endothelial cells, where it anchors organelles to peripheral actin and influences von Willebrand factor multimerization and secretion [#7, #10]. Domain-dissection studies establish the actin-binding domain as the dominant functional element restricting organelle motility and gating exocytosis, with myosin binding playing a secondary role [#2, #14]. MYRIP acts at multiple steps of granule trafficking — inhibiting fast directed movement, enhancing attachment to the plasma membrane, and prolonging immobilization there — with the early steps requiring myosin Va and the immobilization step requiring the C-terminal/actin-exocyst module [#12]. Beyond actin and myosin coupling, MYRIP is an A-kinase anchoring protein that targets type II PKA to secretory organelles and links to the exocyst via Sec6/Sec8 [#4], and incretin/cAMP signaling drives MYRIP phosphorylation, its inducible interaction with myosin Va, and downstream phosphorylation of rabphilin-3A to regulate secretion [#13]. At the active-zone-like tethering machinery, MYRIP recruits granules to cortical actin via myosin VIIa indirectly through RIM-BP2, which associates with Cav1.3, RIM, and Munc13-1 [#15]. Its function in exocytosis is bidirectionally tunable: MYRIP behaves as a negative regulator of Weibel-Palade body exocytosis whose effect is set by Rab27A fractional occupancy relative to the positive regulator Slp4-a [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established MYRIP's foundational identity as a bridge linking Rab27A-positive melanosomes to the actin cytoskeleton, answering how organelle-bound Rab27A connects to motor and cytoskeletal machinery.\",\n      \"evidence\": \"Co-IP and GTP-dependent binding assays with overexpression and immunolocalization in RPE and PC12 cells\",\n      \"pmids\": [\"11964381\", \"12221080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain boundaries defined biochemically but functional necessity in vivo not yet tested\", \"Whether myosin Va versus VIIa preference matters functionally unresolved at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined which MYRIP domain drives function in regulated exocytosis, showing the actin-binding domain — not the myosin Va-binding domain — is the key element controlling insulin secretion.\",\n      \"evidence\": \"siRNA knockdown, domain-mutant overexpression, and point mutagenesis with insulin secretion assays in beta cells\",\n      \"pmids\": [\"14517322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which actin binding restrains versus promotes secretion not resolved\", \"Did not address myosin VIIa or PKA contributions\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished MYRIP as a functional myosin VIIa receptor with higher affinity than for myosin Va, clarifying motor specificity on melanosomes.\",\n      \"evidence\": \"In vitro pulldown, co-IP, Slac2-a depletion with rescue, and melanosome distribution assays in melanocytes\",\n      \"pmids\": [\"15927964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo usage of myosin Va vs VIIa across cell types not established\", \"Mechanism of motor activation not yet mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated the Rab27a-MYRIP-myosin VIIa tripartite complex tethers melanosomes to actin to control directionality, and that MYRIP also functions as an AKAP linking PKA to the exocyst.\",\n      \"evidence\": \"Live-cell imaging of mutant/knockdown RPE cells with cytochalasin D; yeast two-hybrid, pulldown, co-IP in insulin-secreting cells\",\n      \"pmids\": [\"17451552\", \"17827149\", \"17352418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atypical PKA-anchoring mechanism not structurally defined\", \"How AKAP and actin-tethering functions are coordinated unknown\", \"Identity of MYRIP-associated motile small vesicles unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended MYRIP's tethering role to endothelial Weibel-Palade bodies and dissected how distinct domains activate myosin Va versus myosin VIIa, while revealing dynamic stimulus-driven redistribution and proteolysis.\",\n      \"evidence\": \"siRNA in endothelial cells with VWF secretion/multimerization assays; domain mutagenesis in melanocyte transport assays; subcellular fractionation after beta-adrenergic stimulation\",\n      \"pmids\": [\"19270261\", \"19317802\", \"19185850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MMAH vs Myrip-specific insert structural basis of motor selectivity not solved\", \"Protease and PEST-dependent degradation pathway not identified molecularly\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Confirmed a Rab27a/MYRIP/myosin Va tripartite complex on Weibel-Palade bodies governs peripheral positioning and VWF oligomerization quality.\",\n      \"evidence\": \"Co-IP, siRNA, dominant-negative myosin Va, and VWF oligomerization analysis in endothelial cells\",\n      \"pmids\": [\"21740491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab co-IP; reciprocal validation across systems limited\", \"How peripheral positioning mechanistically improves VWF maturation unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved MYRIP as a multi-step regulator of granule trafficking with separable myosin Va-dependent and actin/exocyst-dependent functions, and showed its exocytosis output is bidirectionally tunable via Rab27A occupancy and cAMP/PKA signaling.\",\n      \"evidence\": \"TIRF single-particle tracking with domain mutants in enterochromaffin cells; siRNA/overexpression live-cell exocytosis in endothelial cells; cAMP-driven phosphorylation, co-IP, phosphomutant secretion assays in beta cells\",\n      \"pmids\": [\"22396429\", \"22898601\", \"22993210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) directly phosphorylating MYRIP not pinpointed\", \"How Slp4-a/MYRIP competition is regulated physiologically unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantitatively established the actin-binding domain as dominant over the myosin Va-binding domain for both restricting organelle motility and supporting Ca2+-driven exocytosis.\",\n      \"evidence\": \"MYRIP point mutants disrupting MyoVa and/or actin binding with high-speed live-cell microscopy and actin perturbation in endothelial cells\",\n      \"pmids\": [\"26675235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the actin-dependent exocytosis step not defined\", \"Generalizability beyond Weibel-Palade bodies not tested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified RIM-BP2 as the previously unknown adaptor through which MYRIP/exophilin-8 engages myosin VIIa and active-zone-like exocytic machinery, mechanistically linking cortical actin capture to docking and exocytosis.\",\n      \"evidence\": \"Co-IP with interaction mapping, knockdown and knockout mouse islets, immunofluorescence, and insulin secretion assays\",\n      \"pmids\": [\"28673385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the MYRIP-RIM-BP2-myosin VIIa interaction unresolved\", \"How this complex integrates with the AKAP/PKA module not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYRIP's multiple coupled functions — Rab27A tethering, dual myosin activation, actin binding, PKA anchoring, and RIM-BP2-mediated docking — are spatiotemporally integrated to switch organelle capture into productive exocytosis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length MYRIP with its partners\", \"Direct kinase responsible for cAMP-driven MYRIP phosphorylation unidentified\", \"Mechanism setting the negative-vs-positive regulatory balance at single organelles not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 7, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 5, 14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 7, 12, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"complexes\": [\"Rab27A-MYRIP-myosin VIIa complex\", \"Rab27a-MYRIP-myosin Va complex\", \"exocyst (Sec6/Sec8)\"],\n    \"partners\": [\"RAB27A\", \"MYO7A\", \"MYO5A\", \"RIMBP2\", \"EXOC3\", \"EXOC4\", \"PRKAR2\", \"RPH3A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}