{"gene":"MOB4","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2008,"finding":"MOB4 (Mob3/phocein) was identified as a stable component of the STRIPAK (striatin-interacting phosphatase and kinase) complex by affinity purification/mass spectrometry. The complex contains PP2A catalytic and scaffolding subunits, striatins, STRIP1/2, CCM3, and GCK III family kinases, establishing MOB4 as part of a large PP2A-containing signaling assembly.","method":"Iterative affinity purification / mass spectrometry (AP-MS)","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal AP-MS with multiple orthogonal protein interactions confirmed; widely replicated by subsequent independent studies","pmids":["18782753"],"is_preprint":false},{"year":2011,"finding":"Striatin binds MOB4 (Mob3) at two distinct regions: one N-terminal region including the coiled-coil domain, and one more C-terminal region including the WD-repeat domain. PP2A associates with the coiled-coil/oligomerization domain of striatin and requires striatin oligomerization. Disruption of PP2A binding to striatin causes hyperphosphorylation and activation of striatin-associated Mst3 kinase, establishing that striatin-associated PP2A negatively regulates Mst3 activity and that MOB4 is positioned proximal to both the Mst3-binding site and PP2A, consistent with a regulatory role.","method":"Structure-function analysis of striatin (deletions, point mutations), Co-immunoprecipitation, in-cell phosphorylation assays","journal":"BMC biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple deletion constructs and point mutations with reciprocal Co-IP and phosphorylation readouts in a single focused study","pmids":["21985334"],"is_preprint":false},{"year":2010,"finding":"Drosophila MOB4 (DMob4/Phocein) regulates axonal transport, microtubule network organization, neurite elongation, and synapse formation. Loss-of-function null and hypomorphic alleles show overgrowth of synaptic boutons (similar to endocytotic mutants), defective axonal transport, and disorganized microtubule networks in neurons. Human phocein transgene rescues DMob4 mutant lethality, demonstrating conserved function.","method":"Null and hypomorphic allele generation, in vivo live imaging, genetic rescue with human transgene, RNAi genome-wide screen","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple alleles (null and hypomorphic), in vivo phenotypic analysis with human rescue, multiple orthogonal readouts","pmids":["20392941"],"is_preprint":false},{"year":2008,"finding":"Drosophila Mob4 localizes to the nucleus during interphase and to spindle poles and kinetochores during mitosis. RNAi depletion of Mob4 causes kinetochore fibers (K fibers) to splay apart and fail to maintain focus at spindle poles, both in the presence and absence of functional centrosomes, establishing a role in mitotic spindle pole organization.","method":"RNAi knockdown, time-lapse microscopy, GFP-fusion localization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment plus functional consequence via RNAi; single lab with two orthogonal methods","pmids":["18388316"],"is_preprint":false},{"year":2018,"finding":"MST4 forms a complex with MOB4 in a phosphorylation-dependent manner. The overall structure of the MST4-MOB4 complex resembles that of the MST1-MOB1 complex, but diverged key interface residues allow MST4-MOB4 to disrupt MST1-MOB1 complex assembly through alternative pairing, thereby increasing YAP activity. The MST4-MOB4 complex promotes growth and migration of PANC-1 cells (pro-oncogenic), in contrast to the tumor-suppressor MST1-MOB1 complex.","method":"Co-immunoprecipitation, structural comparison (crystal structure-guided analysis), cell migration/proliferation assays, competitive complex disruption assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — structural analysis combined with Co-IP validation, functional cell-based assays, and mechanistic competition experiments in a single focused study","pmids":["30072378"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the human STRIPAK core (PP2AA, PP2AC, STRN3, STRIP1, MOB4) was determined at 3.2-Å resolution. Unlike canonical trimeric PP2A, STRIPAK contains four copies of STRN3 forming an elongated homotetrameric scaffold that links the complex together, one PP2AA-C heterodimer, one STRIP1, and one MOB4. An inositol hexakisphosphate (IP6) was identified as a structural cofactor of STRIP1. Mutations at key subunit interfaces disrupt STRIPAK integrity and cause aberrant Hippo pathway activation.","method":"Cryo-EM structure determination at 3.2 Å, interface mutagenesis, Hippo pathway activity assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with mutagenesis of interface residues and functional pathway readout; rigorous single study","pmids":["33633399"],"is_preprint":false},{"year":2019,"finding":"In Drosophila, Mob4 and Cka (STRIPAK components) are required for neural stem cell (NSC) reactivation from quiescence. Increased Mob4 and Cka levels recruit PP2A/Mts into a complex with Hippo kinase, resulting in Hippo pathway inhibition and enabling NSC reactivation. MOB4 thus functions as part of a molecular switch coordinating Hippo and InR/PI3K/Akt pathways.","method":"Transcriptome analysis of individual NSCs, genetic loss-of-function, co-complex recruitment assay, epistasis analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus co-complex recruitment assays, single lab with multiple approaches","pmids":["31167138"],"is_preprint":false},{"year":2020,"finding":"In planarians, RNAi inhibition of mob4 dramatically increases posterior body length through expansion of a posterior wnt1+ signaling center in midline muscle cells. This expansion is stem cell-dependent, establishing that MOB4 (as part of STRIPAK) represses Wnt signaling for body axis scaling through control of stem cell differentiation.","method":"RNAi knockdown, epistasis (wnt1 RNAi epistatic to mob4 RNAi), stem cell ablation experiments","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and stem cell dependence established, single lab, multiple orthogonal manipulations","pmids":["31928872"],"is_preprint":false},{"year":2022,"finding":"In zebrafish, loss of mob4 (nonsense mutation) causes impaired actin biogenesis resulting in sarcomere defects and reduced myofibril content, while transgenic overexpression of mob4 increases myofibril content. Genetic interaction analysis revealed that Mob4 acts through the actin-folding chaperonin TRiC to control actin biogenesis and myofibril growth. mob4 mutants also show defective microtubule networks, consistent with TRiC's role in tubulin folding. strn3-deficient mutants show similar characteristics, confirming Mob4 as a STRIPAK core component.","method":"Forward genetic screen, reverse genetics (nonsense mutant), transgenic overexpression, genetic interaction analysis with TRiC","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function plus gain-of-function with genetic interaction analysis, single lab","pmids":["35737712"],"is_preprint":false},{"year":2022,"finding":"MOB3A (an alias for MOB4) bypasses oncogene-induced senescence (OIS) by inhibiting Hippo/MST/LATS signaling. Constitutive membrane localization of MOB3A phenocopies OIS bypass seen with elevated YAP expression. MOB3A and MOB3C (but not canonical MOB1A/B) uniquely permit primary cell proliferation under sustained oncogene signaling. Inhibition of MOB3 family members decreases proliferation and tumor growth of cancer cell lines.","method":"Library screen for OIS bypass, constitutively active localization constructs, cancer cell line knockdown assays, comparison with YAP overexpression","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen plus mechanistic follow-up with localization constructs and Hippo pathway readouts, single lab","pmids":["35046109"],"is_preprint":false},{"year":2023,"finding":"MOB4 KO MCF10A cells display increased collective cell migration with loss of migration orientation in a wound healing assay. Upon wound healing, MOB4 relocalizes to the front edge of leader and follower cells migrating toward the wound. The role of MOB4 in controlling collective migration requires YAP1: MOB4 KO cells fail to activate YAP1, and the phenotype is rescued by constitutively active YAP1.","method":"CRISPR/Cas9 knockout, wound healing assay, live imaging/relocalization, genetic rescue with constitutively active YAP1","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with functional phenotype, direct relocalization imaging, and pathway rescue, single lab","pmids":["41276909"],"is_preprint":false},{"year":2025,"finding":"Striatin-3 and MOB4 were identified as novel Rac1 interactors in Schwann cells by co-immunoprecipitation. Schwann-cell-specific ablation of striatin-3 causes defects in lamellipodia formation; conditional knockout of striatins causes a severe delay in radial sorting. Deletion of Rac1 or striatin-1/3 in Schwann cells causes defects in YAP/TAZ activation and expression of YAP/TAZ co-regulated genes (extracellular matrix receptors), placing MOB4/STRIPAK downstream of Rac1 in Hippo pathway regulation during peripheral nervous system development.","method":"Co-immunoprecipitation (Rac1-striatin-3/MOB4 interaction), conditional Schwann cell knockout (Cre-lox), lamellipodia/radial sorting phenotyping, YAP/TAZ phosphorylation assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus conditional KO with defined cellular and pathway phenotypes, single lab","pmids":["40056414"],"is_preprint":false},{"year":2023,"finding":"Proximity-dependent biotin identification (BioID) mapped the interactome of all seven human MOB proteins including MOB4. MOB4's proximity network was defined; the dataset confirmed known STRIPAK complex interactions for MOB4 and distinguished MOB4's interactome from those of other MOB family members. MOB3C (not MOB4) uniquely interacted with 7 of 10 subunits of the RNase P complex.","method":"BioID proximity labeling in HeLa and HEK293 cells, affinity purification-mass spectrometry validation, pre-tRNA cleavage assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID with AP-MS validation; interactome defined for MOB4 with subfamily-level resolution; single lab","pmids":["37536630"],"is_preprint":false},{"year":2023,"finding":"Drosophila Mob4 is required for male fertility but has no detectable role in female fertility. mob4 RNAi leads to defective spermatid individualization, absence of mature sperm in seminal vesicles, expansion of outer axonemal microtubule doublets (loss of 9+2 linkage), and defective mitochondrial organization. Depletion of STRIPAK components Strip and Cka similarly impairs male fertility. Human MOB4 transgene rescues all Drosophila mob4 RNAi phenotypes, confirming evolutionary conservation.","method":"RNAi knockdown, transmission electron microscopy, genetic rescue with human MOB4 transgene, parallel depletion of other STRIPAK components","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with TEM ultrastructural phenotyping and human transgene rescue, single lab, multiple STRIPAK components tested","pmids":["37259670"],"is_preprint":false},{"year":2013,"finding":"In Neurospora crassa, phosphorylation of MOB-3 (MOB4 ortholog) by the MAP kinase MAK-2 impacts the nuclear accumulation of the cell wall integrity MAP kinase MAK-1. The STRIPAK complex (containing MOB-3/HAM-2/HAM-3/HAM-4/PPG-1/PP2A-A) is assembled at the nuclear envelope and is required for MAK-1 nuclear accumulation. MAK-2-dependent phosphorylation of the N-terminus of MOB-3 is required for proper fruiting body morphology.","method":"Genetic/biochemical analysis, live cell imaging, phosphorylation analysis, nuclear accumulation assays","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic, biochemical, and live cell imaging methods in a single study; ortholog findings with clear mechanistic pathway placement","pmids":["24028079"],"is_preprint":false}],"current_model":"MOB4 (also known as Mob3/phocein) is a core structural and regulatory component of the STRIPAK (striatin-interacting phosphatase and kinase) complex, where it occupies a defined position within the cryo-EM-resolved complex architecture bridging STRN3 and STRIP1; within this complex it modulates PP2A-dependent dephosphorylation of MST kinases, inhibits Hippo/MST/LATS signaling to activate YAP, disrupts the pro-tumor-suppressor MST1-MOB1 complex via competitive pairing with MST4, interacts with Rac1 in Schwann cells to regulate YAP/TAZ-dependent gene expression, and regulates actin biogenesis (via TRiC), microtubule organization, axonal transport, spindle pole focusing, collective cell migration, neural stem cell reactivation, spermatogenesis, and Wnt-dependent body axis scaling across multiple organisms."},"narrative":{"mechanistic_narrative":"MOB4 (Mob3/phocein) is a core structural subunit of the STRIPAK (striatin-interacting phosphatase and kinase) complex, a large PP2A-containing signaling assembly that also includes striatins, STRIP1/2, CCM3, and GCK III family kinases [PMID:18782753]. Within striatin, MOB4 binds at two distinct regions and is positioned proximal to both the STE20-family kinase-binding site and PP2A, where striatin-associated PP2A negatively regulates the associated kinase activity [PMID:21985334]. Cryo-EM of the human STRIPAK core places one MOB4 within an elongated homotetrameric STRN3 scaffold bridging a single PP2AA-C heterodimer and STRIP1, and interface mutations that disrupt complex integrity cause aberrant Hippo pathway activation [PMID:33633399]. Through this architecture MOB4 inhibits Hippo/MST/LATS signaling to activate YAP/TAZ: it forms a phosphorylation-dependent complex with MST4 that competitively disrupts the tumor-suppressor MST1-MOB1 pairing and drives pro-oncogenic growth and migration [PMID:30072378], bypasses oncogene-induced senescence as a Hippo inhibitor [PMID:35046109], and acts downstream of Rac1 in Schwann cells to control YAP/TAZ-dependent gene expression during peripheral nerve development [PMID:40056414]. MOB4-dependent YAP activation also orients collective cell migration, with MOB4 relocalizing to the leading edge of migrating cells [PMID:41276909]. Beyond Hippo signaling, MOB4 governs cytoskeletal biogenesis and organization: it acts through the actin-folding chaperonin TRiC to control actin and tubulin-dependent myofibril growth [PMID:35737712], organizes microtubule networks and axonal transport [PMID:20392941], and focuses kinetochore fibers at mitotic spindle poles [PMID:18388316]. These activities support conserved developmental roles in neural stem cell reactivation [PMID:31167138], Wnt-dependent body axis scaling [PMID:31928872], and spermatogenesis [PMID:37259670], with human MOB4 transgenes rescuing invertebrate loss-of-function phenotypes [PMID:20392941, PMID:37259670].","teleology":[{"year":2008,"claim":"Establishing MOB4's molecular context: it was unknown what assembly MOB4 belonged to, and AP-MS placed it as a stable subunit of the PP2A-containing STRIPAK complex.","evidence":"Iterative affinity purification/mass spectrometry identifying STRIPAK subunits","pmids":["18782753"],"confidence":"High","gaps":["Did not resolve MOB4's spatial position or direct contacts within the complex","No functional consequence of MOB4 within STRIPAK established"]},{"year":2008,"claim":"It was unclear whether MOB4 had a role outside steady-state complexes; localization and RNAi showed it focuses kinetochore fibers at mitotic spindle poles, revealing a cytoskeletal function.","evidence":"RNAi knockdown, time-lapse microscopy, and GFP-fusion localization in Drosophila","pmids":["18388316"],"confidence":"Medium","gaps":["Molecular partners mediating spindle pole focusing not identified","Relationship to STRIPAK not addressed"]},{"year":2010,"claim":"Whether MOB4 had a conserved physiological role in neurons was unknown; loss-of-function alleles tied it to axonal transport, microtubule organization, and synapse formation, with human transgene rescue establishing conservation.","evidence":"Null/hypomorphic alleles, in vivo live imaging, and human phocein rescue in Drosophila","pmids":["20392941"],"confidence":"High","gaps":["Direct molecular mechanism linking MOB4 to microtubule/transport machinery not defined","STRIPAK dependence of neuronal phenotypes not tested"]},{"year":2011,"claim":"How MOB4 is positioned relative to the regulatory enzymes was unresolved; structure-function mapping localized MOB4 binding to two striatin regions near both the kinase-binding site and PP2A, implying a regulatory role in kinase dephosphorylation.","evidence":"Striatin deletion/point mutants, Co-IP, and in-cell phosphorylation assays","pmids":["21985334"],"confidence":"High","gaps":["Direct enzymatic effect of MOB4 on PP2A or kinase activity not isolated","Whether MOB4 binding is required for PP2A-mediated kinase regulation untested"]},{"year":2013,"claim":"Whether MOB4 is itself a regulated node was unknown; in Neurospora, MAK-2-dependent phosphorylation of MOB-3's N-terminus controls nuclear-envelope STRIPAK assembly and downstream MAP kinase nuclear accumulation.","evidence":"Genetic/biochemical analysis, live cell imaging, and phosphorylation assays in Neurospora crassa","pmids":["24028079"],"confidence":"Medium","gaps":["Conservation of MOB4 phosphoregulation in animals not shown","Direct phospho-site consequences on complex assembly not defined"]},{"year":2018,"claim":"How MOB4 modulates Hippo signaling was unclear; structural and competition experiments showed MST4-MOB4 mimics the MST1-MOB1 interface and competitively disrupts the tumor-suppressor complex to activate YAP.","evidence":"Co-IP, structure-guided analysis, competitive complex disruption, and migration/proliferation assays in PANC-1 cells","pmids":["30072378"],"confidence":"High","gaps":["Quantitative contribution of competition versus STRIPAK-PP2A activity not separated","In vivo tumor relevance not established in this study"]},{"year":2019,"claim":"Whether MOB4-STRIPAK governs developmental cell-state transitions was untested; in Drosophila it inhibits Hippo via PP2A recruitment to enable neural stem cell reactivation, integrating Hippo and InR/PI3K/Akt inputs.","evidence":"Single-NSC transcriptomics, genetic loss-of-function, co-complex recruitment, and epistasis in Drosophila","pmids":["31167138"],"confidence":"Medium","gaps":["Direct biochemical demonstration of MOB4-driven PP2A recruitment to Hippo not shown","Crosstalk node with InR/PI3K not molecularly defined"]},{"year":2020,"claim":"Whether MOB4 controls tissue-scale patterning was unknown; planarian RNAi showed it represses a posterior Wnt signaling center to scale body axis through stem cell differentiation.","evidence":"RNAi, wnt1-epistasis, and stem cell ablation in planarians","pmids":["31928872"],"confidence":"Medium","gaps":["Mechanistic link between STRIPAK and Wnt center expansion not defined","Whether this acts via Hippo/YAP not addressed"]},{"year":2022,"claim":"The basis of MOB4's cytoskeletal phenotypes was unresolved; zebrafish genetics showed it acts through the TRiC chaperonin to control actin and tubulin folding, explaining both myofibril and microtubule defects.","evidence":"Forward/reverse genetics, transgenic overexpression, and TRiC genetic interaction in zebrafish","pmids":["35737712"],"confidence":"Medium","gaps":["Direct physical MOB4-TRiC interaction not biochemically demonstrated","Whether this is STRIPAK-dependent or independent unclear"]},{"year":2022,"claim":"Whether MOB4 functionally diverges from canonical MOB1 was unknown; a senescence-bypass screen showed MOB3/MOB4 uniquely inhibit Hippo/MST/LATS to sustain proliferation, with membrane localization phenocopying YAP elevation.","evidence":"OIS-bypass library screen, localization constructs, and cancer line knockdown","pmids":["35046109"],"confidence":"Medium","gaps":["Mechanism of membrane-localized MOB3 action not defined","Distinction between MOB3 family members not fully resolved"]},{"year":2021,"claim":"The architecture of MOB4 within human STRIPAK was unknown; cryo-EM resolved a single MOB4 within a homotetrameric STRN3 scaffold linked to PP2AA-C and STRIP1, with interface mutations causing aberrant Hippo activation.","evidence":"3.2-Å cryo-EM, interface mutagenesis, and Hippo activity assays","pmids":["33633399"],"confidence":"High","gaps":["Conformational/catalytic role of MOB4 within the assembly not mechanistically dissected","How substrate kinases dock onto this architecture not resolved"]},{"year":2023,"claim":"MOB4's broader proximity interactome and its distinction from paralogs were undefined; BioID mapped MOB4's network and confirmed STRIPAK interactions while separating it from MOB3C's RNase P association.","evidence":"BioID proximity labeling with AP-MS validation in HeLa/HEK293","pmids":["37536630"],"confidence":"Medium","gaps":["Functional significance of novel proximity partners untested","Direct versus proximity-only contacts not distinguished"]},{"year":2023,"claim":"Whether MOB4 has a tissue-specific organismal requirement was unknown; Drosophila RNAi showed it is required for male fertility via spermatid individualization, axonemal microtubule integrity, and mitochondrial organization, rescued by human MOB4.","evidence":"RNAi, transmission electron microscopy, and human transgene rescue in Drosophila","pmids":["37259670"],"confidence":"Medium","gaps":["Molecular target driving axonemal/mitochondrial defects not identified","Whether Hippo or cytoskeletal arm dominates not separated"]},{"year":2023,"claim":"How MOB4 directs cell migration was unclear; CRISPR KO showed it orients collective migration through YAP1 activation, with leading-edge relocalization and rescue by constitutively active YAP1.","evidence":"CRISPR/Cas9 KO, wound-healing assay, live imaging, and YAP1 rescue in MCF10A","pmids":["41276909"],"confidence":"Medium","gaps":["Signal triggering MOB4 edge relocalization not defined","Link between migration role and STRIPAK architecture not established"]},{"year":2025,"claim":"The upstream input to MOB4-STRIPAK in nerve development was unknown; Schwann-cell studies identified STRN3/MOB4 as Rac1 interactors required for YAP/TAZ activation and ECM-receptor gene expression during radial sorting.","evidence":"Co-IP and conditional Schwann-cell knockouts with YAP/TAZ phosphorylation readouts","pmids":["40056414"],"confidence":"Medium","gaps":["Direct MOB4-Rac1 contact versus indirect not resolved","Mechanism by which Rac1 modulates STRIPAK activity not defined"]},{"year":null,"claim":"How MOB4 mechanistically toggles between its STRIPAK/Hippo-regulatory role and its TRiC-linked cytoskeletal role, and what governs context-specific partner choice (MST4 competition, Rac1 input, leading-edge relocalization), remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstitution defining MOB4's direct effect on PP2A catalytic output","Direct MOB4-TRiC physical interaction unproven","Determinants of MOB4 subcellular relocalization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,9,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,2,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,14]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,10]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[14]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,9,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7,11,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,9]}],"complexes":["STRIPAK"],"partners":["STRN3","STRIP1","MST4","PP2A","RAC1","TRIC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y3A3","full_name":"MOB-like protein phocein","aliases":["2C4D","Class II mMOB1","Mob1 homolog 3","Mob3","Mps one binder kinase activator-like 3","Preimplantation protein 3"],"length_aa":225,"mass_kda":26.0,"function":"Part of the striatin-interacting phosphatase and kinase (STRIPAK) complexes. STRIPAK complexes have critical roles in protein (de)phosphorylation and are regulators of multiple signaling pathways including Hippo, MAPK, nuclear receptor and cytoskeleton remodeling. Different types of STRIPAK complexes are involved in a variety of biological processes such as cell growth, differentiation, apoptosis, metabolism and immune regulation","subcellular_location":"Cytoplasm, perinuclear region; Membrane; Golgi apparatus, Golgi stack membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y3A3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MOB4","classification":"Common Essential","n_dependent_lines":752,"n_total_lines":1208,"dependency_fraction":0.6225165562913907},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MOB4","total_profiled":1310},"omim":[{"mim_id":"609361","title":"MOB FAMILY, MEMBER 4; MOB4","url":"https://www.omim.org/entry/609361"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MOB4"},"hgnc":{"alias_symbol":["MOB3","DKFZP564M112","CGI-95","2C4D","PHOCN"],"prev_symbol":["PREI3","MOBKL3"]},"alphafold":{"accession":"Q9Y3A3","domains":[{"cath_id":"1.20.140.30","chopping":"83-207","consensus_level":"medium","plddt":95.4407,"start":83,"end":207}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3A3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3A3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3A3-F1-predicted_aligned_error_v6.png","plddt_mean":90.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MOB4","jax_strain_url":"https://www.jax.org/strain/search?query=MOB4"},"sequence":{"accession":"Q9Y3A3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3A3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3A3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3A3"}},"corpus_meta":[{"pmid":"18782753","id":"PMC_18782753","title":"A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein.","date":"2008","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18782753","citation_count":303,"is_preprint":false},{"pmid":"24333164","id":"PMC_24333164","title":"STRIPAK complexes: structure, biological function, and involvement in human diseases.","date":"2013","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24333164","citation_count":185,"is_preprint":false},{"pmid":"21666072","id":"PMC_21666072","title":"Identification and characterization of genes required for cell-to-cell fusion in Neurospora crassa.","date":"2011","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/21666072","citation_count":126,"is_preprint":false},{"pmid":"21985334","id":"PMC_21985334","title":"Protein phosphatase 2a (PP2A) binds within the oligomerization domain of striatin and regulates the phosphorylation and activation of the mammalian Ste20-Like kinase Mst3.","date":"2011","source":"BMC biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21985334","citation_count":89,"is_preprint":false},{"pmid":"24028079","id":"PMC_24028079","title":"HAM-2 and HAM-3 are central for the assembly of the Neurospora STRIPAK complex at the nuclear envelope and regulate nuclear accumulation of the MAP kinase MAK-1 in a MAK-2-dependent manner.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24028079","citation_count":66,"is_preprint":false},{"pmid":"30072378","id":"PMC_30072378","title":"The MST4-MOB4 complex disrupts the MST1-MOB1 complex in the Hippo-YAP pathway and plays a pro-oncogenic role in pancreatic cancer.","date":"2018","source":"The Journal of biological 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STRIPAK (striatin-interacting phosphatase and kinase) complex by affinity purification/mass spectrometry. The complex contains PP2A catalytic and scaffolding subunits, striatins, STRIP1/2, CCM3, and GCK III family kinases, establishing MOB4 as part of a large PP2A-containing signaling assembly.\",\n      \"method\": \"Iterative affinity purification / mass spectrometry (AP-MS)\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal AP-MS with multiple orthogonal protein interactions confirmed; widely replicated by subsequent independent studies\",\n      \"pmids\": [\"18782753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Striatin binds MOB4 (Mob3) at two distinct regions: one N-terminal region including the coiled-coil domain, and one more C-terminal region including the WD-repeat domain. PP2A associates with the coiled-coil/oligomerization domain of striatin and requires striatin oligomerization. Disruption of PP2A binding to striatin causes hyperphosphorylation and activation of striatin-associated Mst3 kinase, establishing that striatin-associated PP2A negatively regulates Mst3 activity and that MOB4 is positioned proximal to both the Mst3-binding site and PP2A, consistent with a regulatory role.\",\n      \"method\": \"Structure-function analysis of striatin (deletions, point mutations), Co-immunoprecipitation, in-cell phosphorylation assays\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple deletion constructs and point mutations with reciprocal Co-IP and phosphorylation readouts in a single focused study\",\n      \"pmids\": [\"21985334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila MOB4 (DMob4/Phocein) regulates axonal transport, microtubule network organization, neurite elongation, and synapse formation. Loss-of-function null and hypomorphic alleles show overgrowth of synaptic boutons (similar to endocytotic mutants), defective axonal transport, and disorganized microtubule networks in neurons. Human phocein transgene rescues DMob4 mutant lethality, demonstrating conserved function.\",\n      \"method\": \"Null and hypomorphic allele generation, in vivo live imaging, genetic rescue with human transgene, RNAi genome-wide screen\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple alleles (null and hypomorphic), in vivo phenotypic analysis with human rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"20392941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila Mob4 localizes to the nucleus during interphase and to spindle poles and kinetochores during mitosis. RNAi depletion of Mob4 causes kinetochore fibers (K fibers) to splay apart and fail to maintain focus at spindle poles, both in the presence and absence of functional centrosomes, establishing a role in mitotic spindle pole organization.\",\n      \"method\": \"RNAi knockdown, time-lapse microscopy, GFP-fusion localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment plus functional consequence via RNAi; single lab with two orthogonal methods\",\n      \"pmids\": [\"18388316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MST4 forms a complex with MOB4 in a phosphorylation-dependent manner. The overall structure of the MST4-MOB4 complex resembles that of the MST1-MOB1 complex, but diverged key interface residues allow MST4-MOB4 to disrupt MST1-MOB1 complex assembly through alternative pairing, thereby increasing YAP activity. The MST4-MOB4 complex promotes growth and migration of PANC-1 cells (pro-oncogenic), in contrast to the tumor-suppressor MST1-MOB1 complex.\",\n      \"method\": \"Co-immunoprecipitation, structural comparison (crystal structure-guided analysis), cell migration/proliferation assays, competitive complex disruption assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural analysis combined with Co-IP validation, functional cell-based assays, and mechanistic competition experiments in a single focused study\",\n      \"pmids\": [\"30072378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the human STRIPAK core (PP2AA, PP2AC, STRN3, STRIP1, MOB4) was determined at 3.2-Å resolution. Unlike canonical trimeric PP2A, STRIPAK contains four copies of STRN3 forming an elongated homotetrameric scaffold that links the complex together, one PP2AA-C heterodimer, one STRIP1, and one MOB4. An inositol hexakisphosphate (IP6) was identified as a structural cofactor of STRIP1. Mutations at key subunit interfaces disrupt STRIPAK integrity and cause aberrant Hippo pathway activation.\",\n      \"method\": \"Cryo-EM structure determination at 3.2 Å, interface mutagenesis, Hippo pathway activity assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with mutagenesis of interface residues and functional pathway readout; rigorous single study\",\n      \"pmids\": [\"33633399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila, Mob4 and Cka (STRIPAK components) are required for neural stem cell (NSC) reactivation from quiescence. Increased Mob4 and Cka levels recruit PP2A/Mts into a complex with Hippo kinase, resulting in Hippo pathway inhibition and enabling NSC reactivation. MOB4 thus functions as part of a molecular switch coordinating Hippo and InR/PI3K/Akt pathways.\",\n      \"method\": \"Transcriptome analysis of individual NSCs, genetic loss-of-function, co-complex recruitment assay, epistasis analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus co-complex recruitment assays, single lab with multiple approaches\",\n      \"pmids\": [\"31167138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In planarians, RNAi inhibition of mob4 dramatically increases posterior body length through expansion of a posterior wnt1+ signaling center in midline muscle cells. This expansion is stem cell-dependent, establishing that MOB4 (as part of STRIPAK) represses Wnt signaling for body axis scaling through control of stem cell differentiation.\",\n      \"method\": \"RNAi knockdown, epistasis (wnt1 RNAi epistatic to mob4 RNAi), stem cell ablation experiments\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and stem cell dependence established, single lab, multiple orthogonal manipulations\",\n      \"pmids\": [\"31928872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish, loss of mob4 (nonsense mutation) causes impaired actin biogenesis resulting in sarcomere defects and reduced myofibril content, while transgenic overexpression of mob4 increases myofibril content. Genetic interaction analysis revealed that Mob4 acts through the actin-folding chaperonin TRiC to control actin biogenesis and myofibril growth. mob4 mutants also show defective microtubule networks, consistent with TRiC's role in tubulin folding. strn3-deficient mutants show similar characteristics, confirming Mob4 as a STRIPAK core component.\",\n      \"method\": \"Forward genetic screen, reverse genetics (nonsense mutant), transgenic overexpression, genetic interaction analysis with TRiC\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function plus gain-of-function with genetic interaction analysis, single lab\",\n      \"pmids\": [\"35737712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MOB3A (an alias for MOB4) bypasses oncogene-induced senescence (OIS) by inhibiting Hippo/MST/LATS signaling. Constitutive membrane localization of MOB3A phenocopies OIS bypass seen with elevated YAP expression. MOB3A and MOB3C (but not canonical MOB1A/B) uniquely permit primary cell proliferation under sustained oncogene signaling. Inhibition of MOB3 family members decreases proliferation and tumor growth of cancer cell lines.\",\n      \"method\": \"Library screen for OIS bypass, constitutively active localization constructs, cancer cell line knockdown assays, comparison with YAP overexpression\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen plus mechanistic follow-up with localization constructs and Hippo pathway readouts, single lab\",\n      \"pmids\": [\"35046109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MOB4 KO MCF10A cells display increased collective cell migration with loss of migration orientation in a wound healing assay. Upon wound healing, MOB4 relocalizes to the front edge of leader and follower cells migrating toward the wound. The role of MOB4 in controlling collective migration requires YAP1: MOB4 KO cells fail to activate YAP1, and the phenotype is rescued by constitutively active YAP1.\",\n      \"method\": \"CRISPR/Cas9 knockout, wound healing assay, live imaging/relocalization, genetic rescue with constitutively active YAP1\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with functional phenotype, direct relocalization imaging, and pathway rescue, single lab\",\n      \"pmids\": [\"41276909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Striatin-3 and MOB4 were identified as novel Rac1 interactors in Schwann cells by co-immunoprecipitation. Schwann-cell-specific ablation of striatin-3 causes defects in lamellipodia formation; conditional knockout of striatins causes a severe delay in radial sorting. Deletion of Rac1 or striatin-1/3 in Schwann cells causes defects in YAP/TAZ activation and expression of YAP/TAZ co-regulated genes (extracellular matrix receptors), placing MOB4/STRIPAK downstream of Rac1 in Hippo pathway regulation during peripheral nervous system development.\",\n      \"method\": \"Co-immunoprecipitation (Rac1-striatin-3/MOB4 interaction), conditional Schwann cell knockout (Cre-lox), lamellipodia/radial sorting phenotyping, YAP/TAZ phosphorylation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus conditional KO with defined cellular and pathway phenotypes, single lab\",\n      \"pmids\": [\"40056414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Proximity-dependent biotin identification (BioID) mapped the interactome of all seven human MOB proteins including MOB4. MOB4's proximity network was defined; the dataset confirmed known STRIPAK complex interactions for MOB4 and distinguished MOB4's interactome from those of other MOB family members. MOB3C (not MOB4) uniquely interacted with 7 of 10 subunits of the RNase P complex.\",\n      \"method\": \"BioID proximity labeling in HeLa and HEK293 cells, affinity purification-mass spectrometry validation, pre-tRNA cleavage assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID with AP-MS validation; interactome defined for MOB4 with subfamily-level resolution; single lab\",\n      \"pmids\": [\"37536630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Drosophila Mob4 is required for male fertility but has no detectable role in female fertility. mob4 RNAi leads to defective spermatid individualization, absence of mature sperm in seminal vesicles, expansion of outer axonemal microtubule doublets (loss of 9+2 linkage), and defective mitochondrial organization. Depletion of STRIPAK components Strip and Cka similarly impairs male fertility. Human MOB4 transgene rescues all Drosophila mob4 RNAi phenotypes, confirming evolutionary conservation.\",\n      \"method\": \"RNAi knockdown, transmission electron microscopy, genetic rescue with human MOB4 transgene, parallel depletion of other STRIPAK components\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with TEM ultrastructural phenotyping and human transgene rescue, single lab, multiple STRIPAK components tested\",\n      \"pmids\": [\"37259670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Neurospora crassa, phosphorylation of MOB-3 (MOB4 ortholog) by the MAP kinase MAK-2 impacts the nuclear accumulation of the cell wall integrity MAP kinase MAK-1. The STRIPAK complex (containing MOB-3/HAM-2/HAM-3/HAM-4/PPG-1/PP2A-A) is assembled at the nuclear envelope and is required for MAK-1 nuclear accumulation. MAK-2-dependent phosphorylation of the N-terminus of MOB-3 is required for proper fruiting body morphology.\",\n      \"method\": \"Genetic/biochemical analysis, live cell imaging, phosphorylation analysis, nuclear accumulation assays\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic, biochemical, and live cell imaging methods in a single study; ortholog findings with clear mechanistic pathway placement\",\n      \"pmids\": [\"24028079\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MOB4 (also known as Mob3/phocein) is a core structural and regulatory component of the STRIPAK (striatin-interacting phosphatase and kinase) complex, where it occupies a defined position within the cryo-EM-resolved complex architecture bridging STRN3 and STRIP1; within this complex it modulates PP2A-dependent dephosphorylation of MST kinases, inhibits Hippo/MST/LATS signaling to activate YAP, disrupts the pro-tumor-suppressor MST1-MOB1 complex via competitive pairing with MST4, interacts with Rac1 in Schwann cells to regulate YAP/TAZ-dependent gene expression, and regulates actin biogenesis (via TRiC), microtubule organization, axonal transport, spindle pole focusing, collective cell migration, neural stem cell reactivation, spermatogenesis, and Wnt-dependent body axis scaling across multiple organisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MOB4 (Mob3/phocein) is a core structural subunit of the STRIPAK (striatin-interacting phosphatase and kinase) complex, a large PP2A-containing signaling assembly that also includes striatins, STRIP1/2, CCM3, and GCK III family kinases [#0]. Within striatin, MOB4 binds at two distinct regions and is positioned proximal to both the STE20-family kinase-binding site and PP2A, where striatin-associated PP2A negatively regulates the associated kinase activity [#1]. Cryo-EM of the human STRIPAK core places one MOB4 within an elongated homotetrameric STRN3 scaffold bridging a single PP2AA-C heterodimer and STRIP1, and interface mutations that disrupt complex integrity cause aberrant Hippo pathway activation [#5]. Through this architecture MOB4 inhibits Hippo/MST/LATS signaling to activate YAP/TAZ: it forms a phosphorylation-dependent complex with MST4 that competitively disrupts the tumor-suppressor MST1-MOB1 pairing and drives pro-oncogenic growth and migration [#4], bypasses oncogene-induced senescence as a Hippo inhibitor [#9], and acts downstream of Rac1 in Schwann cells to control YAP/TAZ-dependent gene expression during peripheral nerve development [#11]. MOB4-dependent YAP activation also orients collective cell migration, with MOB4 relocalizing to the leading edge of migrating cells [#10]. Beyond Hippo signaling, MOB4 governs cytoskeletal biogenesis and organization: it acts through the actin-folding chaperonin TRiC to control actin and tubulin-dependent myofibril growth [#8], organizes microtubule networks and axonal transport [#2], and focuses kinetochore fibers at mitotic spindle poles [#3]. These activities support conserved developmental roles in neural stem cell reactivation [#6], Wnt-dependent body axis scaling [#7], and spermatogenesis [#13], with human MOB4 transgenes rescuing invertebrate loss-of-function phenotypes [#2, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing MOB4's molecular context: it was unknown what assembly MOB4 belonged to, and AP-MS placed it as a stable subunit of the PP2A-containing STRIPAK complex.\",\n      \"evidence\": \"Iterative affinity purification/mass spectrometry identifying STRIPAK subunits\",\n      \"pmids\": [\"18782753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve MOB4's spatial position or direct contacts within the complex\", \"No functional consequence of MOB4 within STRIPAK established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"It was unclear whether MOB4 had a role outside steady-state complexes; localization and RNAi showed it focuses kinetochore fibers at mitotic spindle poles, revealing a cytoskeletal function.\",\n      \"evidence\": \"RNAi knockdown, time-lapse microscopy, and GFP-fusion localization in Drosophila\",\n      \"pmids\": [\"18388316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners mediating spindle pole focusing not identified\", \"Relationship to STRIPAK not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether MOB4 had a conserved physiological role in neurons was unknown; loss-of-function alleles tied it to axonal transport, microtubule organization, and synapse formation, with human transgene rescue establishing conservation.\",\n      \"evidence\": \"Null/hypomorphic alleles, in vivo live imaging, and human phocein rescue in Drosophila\",\n      \"pmids\": [\"20392941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular mechanism linking MOB4 to microtubule/transport machinery not defined\", \"STRIPAK dependence of neuronal phenotypes not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"How MOB4 is positioned relative to the regulatory enzymes was unresolved; structure-function mapping localized MOB4 binding to two striatin regions near both the kinase-binding site and PP2A, implying a regulatory role in kinase dephosphorylation.\",\n      \"evidence\": \"Striatin deletion/point mutants, Co-IP, and in-cell phosphorylation assays\",\n      \"pmids\": [\"21985334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic effect of MOB4 on PP2A or kinase activity not isolated\", \"Whether MOB4 binding is required for PP2A-mediated kinase regulation untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether MOB4 is itself a regulated node was unknown; in Neurospora, MAK-2-dependent phosphorylation of MOB-3's N-terminus controls nuclear-envelope STRIPAK assembly and downstream MAP kinase nuclear accumulation.\",\n      \"evidence\": \"Genetic/biochemical analysis, live cell imaging, and phosphorylation assays in Neurospora crassa\",\n      \"pmids\": [\"24028079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of MOB4 phosphoregulation in animals not shown\", \"Direct phospho-site consequences on complex assembly not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"How MOB4 modulates Hippo signaling was unclear; structural and competition experiments showed MST4-MOB4 mimics the MST1-MOB1 interface and competitively disrupts the tumor-suppressor complex to activate YAP.\",\n      \"evidence\": \"Co-IP, structure-guided analysis, competitive complex disruption, and migration/proliferation assays in PANC-1 cells\",\n      \"pmids\": [\"30072378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of competition versus STRIPAK-PP2A activity not separated\", \"In vivo tumor relevance not established in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether MOB4-STRIPAK governs developmental cell-state transitions was untested; in Drosophila it inhibits Hippo via PP2A recruitment to enable neural stem cell reactivation, integrating Hippo and InR/PI3K/Akt inputs.\",\n      \"evidence\": \"Single-NSC transcriptomics, genetic loss-of-function, co-complex recruitment, and epistasis in Drosophila\",\n      \"pmids\": [\"31167138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical demonstration of MOB4-driven PP2A recruitment to Hippo not shown\", \"Crosstalk node with InR/PI3K not molecularly defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether MOB4 controls tissue-scale patterning was unknown; planarian RNAi showed it represses a posterior Wnt signaling center to scale body axis through stem cell differentiation.\",\n      \"evidence\": \"RNAi, wnt1-epistasis, and stem cell ablation in planarians\",\n      \"pmids\": [\"31928872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between STRIPAK and Wnt center expansion not defined\", \"Whether this acts via Hippo/YAP not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The basis of MOB4's cytoskeletal phenotypes was unresolved; zebrafish genetics showed it acts through the TRiC chaperonin to control actin and tubulin folding, explaining both myofibril and microtubule defects.\",\n      \"evidence\": \"Forward/reverse genetics, transgenic overexpression, and TRiC genetic interaction in zebrafish\",\n      \"pmids\": [\"35737712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical MOB4-TRiC interaction not biochemically demonstrated\", \"Whether this is STRIPAK-dependent or independent unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether MOB4 functionally diverges from canonical MOB1 was unknown; a senescence-bypass screen showed MOB3/MOB4 uniquely inhibit Hippo/MST/LATS to sustain proliferation, with membrane localization phenocopying YAP elevation.\",\n      \"evidence\": \"OIS-bypass library screen, localization constructs, and cancer line knockdown\",\n      \"pmids\": [\"35046109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of membrane-localized MOB3 action not defined\", \"Distinction between MOB3 family members not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The architecture of MOB4 within human STRIPAK was unknown; cryo-EM resolved a single MOB4 within a homotetrameric STRN3 scaffold linked to PP2AA-C and STRIP1, with interface mutations causing aberrant Hippo activation.\",\n      \"evidence\": \"3.2-Å cryo-EM, interface mutagenesis, and Hippo activity assays\",\n      \"pmids\": [\"33633399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational/catalytic role of MOB4 within the assembly not mechanistically dissected\", \"How substrate kinases dock onto this architecture not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"MOB4's broader proximity interactome and its distinction from paralogs were undefined; BioID mapped MOB4's network and confirmed STRIPAK interactions while separating it from MOB3C's RNase P association.\",\n      \"evidence\": \"BioID proximity labeling with AP-MS validation in HeLa/HEK293\",\n      \"pmids\": [\"37536630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of novel proximity partners untested\", \"Direct versus proximity-only contacts not distinguished\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether MOB4 has a tissue-specific organismal requirement was unknown; Drosophila RNAi showed it is required for male fertility via spermatid individualization, axonemal microtubule integrity, and mitochondrial organization, rescued by human MOB4.\",\n      \"evidence\": \"RNAi, transmission electron microscopy, and human transgene rescue in Drosophila\",\n      \"pmids\": [\"37259670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target driving axonemal/mitochondrial defects not identified\", \"Whether Hippo or cytoskeletal arm dominates not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How MOB4 directs cell migration was unclear; CRISPR KO showed it orients collective migration through YAP1 activation, with leading-edge relocalization and rescue by constitutively active YAP1.\",\n      \"evidence\": \"CRISPR/Cas9 KO, wound-healing assay, live imaging, and YAP1 rescue in MCF10A\",\n      \"pmids\": [\"41276909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal triggering MOB4 edge relocalization not defined\", \"Link between migration role and STRIPAK architecture not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The upstream input to MOB4-STRIPAK in nerve development was unknown; Schwann-cell studies identified STRN3/MOB4 as Rac1 interactors required for YAP/TAZ activation and ECM-receptor gene expression during radial sorting.\",\n      \"evidence\": \"Co-IP and conditional Schwann-cell knockouts with YAP/TAZ phosphorylation readouts\",\n      \"pmids\": [\"40056414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MOB4-Rac1 contact versus indirect not resolved\", \"Mechanism by which Rac1 modulates STRIPAK activity not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MOB4 mechanistically toggles between its STRIPAK/Hippo-regulatory role and its TRiC-linked cytoskeletal role, and what governs context-specific partner choice (MST4 competition, Rac1 input, leading-edge relocalization), remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution defining MOB4's direct effect on PP2A catalytic output\", \"Direct MOB4-TRiC physical interaction unproven\", \"Determinants of MOB4 subcellular relocalization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 9, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 9, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7, 11, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"complexes\": [\"STRIPAK\"],\n    \"partners\": [\"STRN3\", \"STRIP1\", \"MST4\", \"PP2A\", \"Rac1\", \"TRiC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}