{"gene":"MOB1A","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1998,"finding":"MOB1 (yeast) physically binds DBF2 in vivo and in vitro in the absence of other yeast proteins; this interaction is required for the late mitotic function of DBF2, as temperature-sensitive MOB1 mutants that cannot bind DBF2 fail to execute the telophase/G1 transition. Overexpression of MOB1 suppresses lethality of dbf2Δ dbf20Δ double deletion, indicating DBF2 acts through MOB1.","method":"Two-hybrid screen, co-immunoprecipitation, in vitro binding, genetic suppression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vivo and in vitro binding plus multiple genetic epistasis experiments in a single focused study","pmids":["9528782"],"is_preprint":false},{"year":1998,"finding":"Yeast MOB1 is a phosphoprotein in vivo and a substrate for the Mps1p kinase in vitro; loss-of-function mob1 alleles cause late nuclear division arrest, and MOB1 shows genetic interactions with LTE1, CDC5, and CDC15, placing it in the mitotic exit pathway.","method":"Two-hybrid screen, in vitro kinase assay, conditional allele analysis, genetic interaction","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay plus multiple genetic interactions, foundational paper replicated by subsequent work","pmids":["9436989"],"is_preprint":false},{"year":2001,"finding":"Cdc15 kinase activates the Dbf2-Mob1 complex in vitro only when Dbf2 is bound to Mob1; Cdc15 phosphorylates conserved sites Ser-374 and Thr-544 on Dbf2, and Mob1 enables Cdc15 to phosphorylate these critical sites. Dbf2 kinase activity in vivo depends on Tem1, Cdc15, and Mob1.","method":"In vitro kinase reconstitution, site-directed mutagenesis, in vivo activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis of phosphoacceptor sites, validated in vivo","pmids":["11404483"],"is_preprint":false},{"year":2001,"finding":"Genetic epistasis in budding yeast places Tem1 upstream of Cdc15, which functions upstream of Mob1 and Dbf2 in the mitotic exit network; Dbf2 kinase activity and actin ring formation at the bud neck are both controlled by the same MEN components including Mob1.","method":"Genetic epistasis, Dbf2 kinase activity assays, actin ring visualization","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic epistasis with kinase readout, replicated ordering consistent with prior reconstitution data","pmids":["11378390"],"is_preprint":false},{"year":2001,"finding":"Mammalian MOB1 (mMOB1) associates with striatin/SG2NA-PP2A complexes; PP2A dephosphorylates mMOB1 since PP2A inhibition with okadaic acid induces serine phosphorylation of PP2A-associated mMOB1. mMOB1 localizes adjacent to the nuclear membrane in murine fibroblasts.","method":"Co-immunoprecipitation, pharmacological PP2A inhibition, indirect immunofluorescence, mass spectrometry identification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and pharmacological modulation, single lab","pmids":["11319234"],"is_preprint":false},{"year":2001,"finding":"Dbf2 and Mob1 (yeast) localize to spindle pole bodies in anaphase and then relocalize to the bud neck just prior to actin ring assembly; bud-neck localization but not SPB localization of Dbf2 is inhibited by the Bub2 spindle checkpoint, and neck localization of both Dbf2 and Mob1 depends on Cdc14 activity.","method":"Fluorescence microscopy of tagged proteins, genetic analysis with checkpoint and cdc14 mutants","journal":"Genes & genetic systems","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional epistasis to checkpoint and phosphatase, single lab","pmids":["11434459"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of human MOB1A reveals a four-helix bundle stabilized by a bound zinc atom; the N-terminal helix and adjacent elements form an evolutionarily conserved surface with strong negative electrostatic potential that is targeted by temperature-sensitive yeast MOB1 alleles, suggesting this surface mediates electrostatic interactions with basic regions of kinase partners.","method":"X-ray crystallography","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation via yeast conditional alleles, and structure corroborated by NMR study (PMID 15001360)","pmids":["12962634"],"is_preprint":false},{"year":2004,"finding":"NMR solution structure of Xenopus Mob1 shows a four-helix bundle with a zinc-binding site; chemical shift perturbations upon addition of a peptide from the N-terminal regulatory domain of NDR kinase map the NDR-binding interface to the conserved acidic surface of Mob1, confirming this surface mediates kinase interaction.","method":"Heteronuclear multidimensional NMR, chemical shift perturbation mapping","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with direct binding interface mapping, orthogonal to crystal structure data","pmids":["15001360"],"is_preprint":false},{"year":2005,"finding":"The Dbf2-Mob1 kinase complex preferentially phosphorylates substrates containing an RXXS motif (serine over threonine required; arginine at -3 position essential and cannot be substituted by lysine), as determined by peptide library selection and proteome chip screening.","method":"Peptide library selection, phosphorylation of optimal peptide variants, proteome microarray","journal":"BMC biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical substrate specificity defined by multiple orthogonal methods (peptide library + proteome chip)","pmids":["16242037"],"is_preprint":false},{"year":2006,"finding":"Human MOB1 activates LATS1 kinase when membrane-targeted (but not when merely co-expressed); activation requires intact phosphorylation sites in LATS1's activation segment and hydrophobic motif, and occurs within minutes of membrane association. A conserved MOB1-binding motif within LATS1 was identified.","method":"Co-expression with membrane-targeting constructs, kinase activity assays, site-directed mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase assay with mutagenesis and membrane-targeting manipulation, single lab","pmids":["16674920"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of S. cerevisiae Mob1 (full-length, 2.0 Å) reveals N-terminal structural elements (helix H0, strand S0, strand S-1); H0 mediates intermolecular homodimerization and S0 binds intramolecularly across the Dbf2-binding site. In vivo functional analysis shows Mob1 mutants targeting H0 or its binding site are biologically compromised.","method":"X-ray crystallography, in vivo yeast functional analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with in vivo functional validation of specific structural elements, single lab","pmids":["16934835"],"is_preprint":false},{"year":2008,"finding":"MST2 phosphorylates MOB1 at Thr74 in vitro; phosphorylation at Thr74 (but not Thr181) is essential for the formation of a MOB1-MST2-NDR1 scaffold complex and for full NDR1 activation. MOB1-T74A fails to enhance its interaction with NDR1 upon okadaic acid treatment. Knockdown of MOB1 or MST2 abolishes NDR1 activation in cells.","method":"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, RNAi knockdown, NDR1 kinase activity assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis plus cell-based epistasis, multiple orthogonal methods","pmids":["18362890"],"is_preprint":false},{"year":2009,"finding":"The Dbf2-Mob1 kinase complex directly phosphorylates Cdc14 phosphatase on serine and threonine residues adjacent to its nuclear localization signal (NLS), thereby abrogating NLS activity and promoting Cdc14 relocalization from the nucleolus to the cytoplasm during mitotic exit.","method":"In vitro kinase assay, mass spectrometry phosphorylation site mapping, nuclear localization assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus MS identification of sites plus functional NLS assay, single lab","pmids":["19221193"],"is_preprint":false},{"year":2009,"finding":"Human Mob1 localizes to spindle poles and kinetochores in early mitosis and to the spindle midzone during cytokinesis; chromosomal passenger complex (CPC) disruption abolishes Mob1 recruitment to kinetochores (but not spindle poles), while Plk1 depletion eliminates spindle-pole Mob1. Mob1 depletion delays CPC and MKLP2 relocalization to the spindle midzone in early anaphase.","method":"Immunofluorescence, RNAi depletion, live-cell imaging","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional epistasis to CPC and Plk1, single lab","pmids":["19955215"],"is_preprint":false},{"year":2012,"finding":"Human Mob1A and Mob1B are required for cytokinetic abscission; RNAi depletion causes abscission failure due to hyper-stabilization of microtubules in the midbody region. Mob1 depletion also increases cell motility and induces prolonged centriole separation in G1; conversely, Mob1A or Mob1B overexpression prevents centrosome splitting.","method":"RNAi depletion, microtubule stability assay, live-cell imaging, cytokinesis assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with specific cellular phenotype and mechanistic readout (microtubule stability), single lab","pmids":["22454515"],"is_preprint":false},{"year":2013,"finding":"The RING E3 ubiquitin ligase praja2 ubiquitylates and targets MOB1 for proteasomal degradation; this degradation attenuates LATS/NDR kinase activity and the Hippo tumor-suppressor cascade, sustaining glioblastoma growth in vivo.","method":"Co-immunoprecipitation, ubiquitylation assay, proteasome inhibition, in vivo tumor growth","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, ubiquitylation assay, and in vivo rescue, single lab but multiple methods","pmids":["23652010"],"is_preprint":false},{"year":2015,"finding":"Human MOB1 binds autophosphorylated docking motifs in active MST2, enabling MOB1 phosphorylation by MST2; phosphorylated MOB1 undergoes conformational activation and binds LATS1. Crystal structures of phospho-MST2-MOB1 and phospho-MOB1-LATS1 complexes reveal phosphorylation-dependent binding events. MOB1 mediates LATS1 activation through dynamic scaffolding and allosteric mechanisms.","method":"Biochemical binding assays, in vitro kinase assays, X-ray crystallography, functional epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with biochemical reconstitution and mutagenesis, multiple orthogonal methods in one study","pmids":["26108669"],"is_preprint":false},{"year":2015,"finding":"Mob1a/Mob1b double knockout in mouse liver causes hyperproliferation, hepatocyte dedifferentiation, enhanced epithelial-mesenchymal transition, and development of liver cancers; these phenotypes are strongly dependent on YAP1 and partially on TAZ and TGF-β2/3 signaling, placing MOB1A/B as the critical hub of Hippo signaling upstream of LATS-YAP1/TAZ.","method":"Conditional knockout mice, genetic epistasis (Yap1 rescue), drug screening, cell culture assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse KO with YAP1-dependent epistasis rescue, multiple cellular phenotypes assessed","pmids":["26699479"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of full-length MOB1B reveals an autoinhibited conformation where the N-terminal Switch helix (stabilized by SN strand β-sheet formation) blocks the LATS1-binding surface. MST1/2-mediated phosphorylation of Thr12 and Thr35 structurally relieves autoinhibition via a 'pull-the-string' mechanism, enabling LATS1 binding.","method":"X-ray crystallography of full-length MOB1B, complex with LATS1 NTR, biochemical validation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of autoinhibited and complex forms with mechanistic explanation, single lab","pmids":["27335147"],"is_preprint":false},{"year":2017,"finding":"MOB1A phosphopeptide-binding specificity is highly complementary to MST1/2 substrate phosphorylation consensus; autophosphorylation of MST1/2 on multiple threonine residues provides several MOB1A-binding sites with varying affinities. Crystal structures of MOB1A with two MST1 phosphopeptides define the phosphopeptide-binding consensus. Phosphopeptide-binding is conserved in six of seven human MOB family members.","method":"Proteomics, peptide arrays, biochemical binding assays, X-ray crystallography, interaction proteomics","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including crystal structures, peptide arrays, and proteomics in one study","pmids":["28373298"],"is_preprint":false},{"year":2017,"finding":"MOB1 phosphorylation by upstream MST kinases differentially regulates its two protein interaction surfaces: phosphorylation promotes binding to MST via the phosphopeptide-binding surface while modulating LATS/NDR binding at a distinct surface. MOB1A also associates in a phosphorylation-dependent manner with PP6 phosphatase and Rho guanine exchange factor complexes (DOCK6-8) through mechanisms distinct from MST1/2 binding.","method":"Biochemical assays, biophysical binding measurements, mutagenesis, structural analysis, interaction proteomics","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1 / Moderate — comprehensive biochemical, biophysical, mutational and structural analyses with proteomics validation","pmids":["28373297"],"is_preprint":false},{"year":2017,"finding":"MOB1/Warts (LATS) binding is essential for tumor suppression, tissue growth control, and development in Drosophila and human cells, while stable MOB1/Hippo (MST) binding is dispensable and MOB1/Trc (NDR) binding alone is insufficient. Crystal structure of the MOB1/NDR2 complex defines key residues for differential binding to Hippo core kinases.","method":"Crystal structure, mutagenesis, Drosophila genetic analysis, human cancer cell studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with selective loss-of-interaction variants validated in multiple model systems","pmids":["28947795"],"is_preprint":false},{"year":2019,"finding":"Kindlin-2 (focal adhesion molecule) interacts with MOB1 and promotes its degradation by enhancing MOB1-praja2 (E3 ligase) interaction; this inhibits LATS1 phosphorylation and YAP phosphorylation, promoting YAP nuclear translocation. Kindlin-2 depletion activates Hippo/YAP signaling and alleviates renal fibrosis in vivo.","method":"Co-immunoprecipitation, ubiquitylation assay, MOB1 degradation assay, mouse knockout with UUO model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with functional degradation assay and in vivo rescue, single lab","pmids":["31825843"],"is_preprint":false},{"year":2019,"finding":"PR55α regulatory subunit of PP2A inhibits MOB1-triggered autoactivation of LATS1/2 kinases, thereby promoting YAP activation; PR55α also directly interacts with YAP. This identifies a PP2A-MOB1-LATS1/2 axis controlling YAP in pancreatic cancer cells.","method":"Co-immunoprecipitation, kinase activity assay, RNAi knockdown, anchorage-independent growth assay","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase activity assay with co-IP and RNAi, single lab","pmids":["31659153"],"is_preprint":false},{"year":2018,"finding":"MOB1 stability is regulated by the PTEN-GSK3β axis; GSK3β phosphorylates MOB1 on Ser146, targeting it for ubiquitin-proteasome degradation. PTEN knockdown (via PI3K-AKT) suppresses GSK3β and stabilizes MOB1 protein, promoting neurite outgrowth.","method":"In vitro kinase assay, site-directed mutagenesis, ubiquitin-proteasome assay, lentiviral in vivo silencing","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis and proteasome assay, single lab","pmids":["30069702"],"is_preprint":false},{"year":2020,"finding":"The Legionella pneumophila effector kinase LegK7 uses MOB1A as both a substrate and an allosteric activator; MOB1A binding to the LegK7 kinase domain reorients the two kinase lobes into an ATP-binding-compatible closed conformation. The MOB1A N-terminal extension (NTE) serves as a docking site for downstream substrates (YAP1). Crystal structure of the LegK7-MOB1A complex was determined.","method":"X-ray crystallography, in vitro kinase assay, mutagenesis of interface residues, cell-based phosphorylation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and in vitro/cell-based validation of allosteric mechanism","pmids":["32513747"],"is_preprint":false},{"year":2021,"finding":"EGFR promotes tyrosine phosphorylation of MOB1 (a core Hippo component) and inactivates LATS1/2 independently of MST1/2, thereby activating YAP/TAZ in head and neck squamous cell carcinoma cells.","method":"Phosphorylation assays, kinase inhibition (erlotinib), RNAi and loss-of-function experiments, transcriptomic analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation assays with inhibitor and RNAi epistasis, single lab","pmids":["34725466"],"is_preprint":false},{"year":2022,"finding":"MOB1 is acetylated at Lys11 by acetyltransferase CBP and deacetylated by HDAC6; MOB1-K11 acetylation stabilizes MOB1 by reducing its binding to E3 ligase Praja2 and subsequent ubiquitination, and also increases MOB1 phosphorylation and activates LATS1. Oxidative stress promotes MOB1 acetylation by suppressing CBP degradation, independently of MST1/2 kinase activity.","method":"Co-immunoprecipitation, ubiquitylation assay, in vitro acetylation assay, site-directed mutagenesis (K11R), in vitro and in vivo tumor assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical acetylation/ubiquitylation assays with mutagenesis and functional in vivo validation, multiple orthogonal methods","pmids":["35349706"],"is_preprint":false},{"year":2022,"finding":"The lncRNA WEE2-AS1 (from CAF-derived exosomes) functions as a scaffold bridging MOB1A and E3 ligase praja2, leading to MOB1A ubiquitin-proteasome degradation, Hippo pathway inhibition, and increased YAP nuclear translocation in colorectal cancer cells.","method":"Co-immunoprecipitation, RNA-protein interaction assay, ubiquitylation assay, in vivo tumor model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitylation assay with in vivo validation, single lab","pmids":["36123327"],"is_preprint":false},{"year":2010,"finding":"Among all seven human MOB family members, only hMOB1A and hMOB1B interact with both LATS1 and LATS2 in vitro and in vivo; overexpression of hMOB1 in cancer cells activates LATS kinase activity and inhibits proliferation or causes apoptosis, with membrane-targeted hMOB1 producing stronger effects.","method":"Co-immunoprecipitation, in vitro binding, kinase activity assay, overexpression and shRNA knockdown in cancer cells","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with kinase activity assay, comprehensive comparison of MOB family members, single lab","pmids":["19739119"],"is_preprint":false}],"current_model":"MOB1A is a conserved scaffold/adaptor protein and core component of the Hippo tumor-suppressor pathway that functions by: (1) binding autophosphorylated MST1/2 kinases via a phosphopeptide-recognition surface, relieving its own autoinhibition upon MST-mediated phosphorylation at Thr12/Thr35; (2) allosterically activating LATS1/2 and NDR kinases through a distinct interaction surface, thereby promoting YAP/TAZ phosphorylation and cytoplasmic retention; (3) serving as a substrate for multiple post-translational modifications—phosphorylation by MST1/2 (activating), ubiquitylation by praja2 E3 ligase (destabilizing, counteracted by acetylation at K11 by CBP/deacetylation by HDAC6, and by phosphorylation by GSK3β at Ser146)—that collectively tune its abundance and activity; and (4) directly activating NDR/LATS-family kinases (orthologous to yeast Dbf2) in the mitotic exit network to phosphorylate substrates (e.g., Cdc14/NLS) and regulate cytokinesis, with MOB1-LATS/Warts binding being the interaction essential for tumor suppression."},"narrative":{"mechanistic_narrative":"MOB1A is a conserved kinase coactivator and phosphorylation-controlled scaffold that operates as a core hub of the Hippo tumor-suppressor pathway and the mitotic exit/cytokinesis machinery [PMID:26108669, PMID:26699479]. The protein folds as a zinc-stabilized four-helix bundle whose conserved, electrostatically negative surface engages basic regulatory regions of partner kinases [PMID:12962634, PMID:15001360]. In the activation cycle, autophosphorylated MST1/2 present docking phosphomotifs that MOB1A recognizes through a dedicated phosphopeptide-binding surface, and MST-mediated phosphorylation of MOB1A (e.g. Thr12/Thr35) relieves an N-terminal Switch-helix autoinhibition by a 'pull-the-string' mechanism, exposing a distinct surface for LATS/NDR kinase binding [PMID:26108669, PMID:27335147, PMID:28373298]; through dynamic scaffolding and allostery MOB1A then activates LATS1/2 and NDR kinases [PMID:16674920, PMID:18362890, PMID:26108669]. The MOB1-LATS(Warts) interaction is the binding event essential for tumor suppression and growth control, whereas stable MOB1-MST binding is dispensable and MOB1-NDR binding alone is insufficient [PMID:28947795]. Genetically, MOB1A/B act as the critical node upstream of LATS-YAP1/TAZ, since their loss in mouse liver drives YAP1-dependent hyperproliferation, dedifferentiation, EMT, and tumorigenesis [PMID:26699479]. MOB1A abundance is tuned by competing post-translational modifications: praja2-mediated ubiquitylation drives proteasomal degradation [PMID:23652010], opposed by CBP/HDAC6-controlled Lys11 acetylation that blocks praja2 binding and stabilizes the protein [PMID:35349706], while GSK3β phosphorylation at Ser146 promotes its degradation [PMID:30069702]. This conserved coactivator role originated in the yeast mitotic exit network, where Mob1 binds and activates the Dbf2 kinase—itself activated by Cdc15 downstream of Tem1—and the Dbf2-Mob1 complex phosphorylates RXXS-motif substrates including Cdc14 to control nucleolar release and cytokinesis [PMID:9528782, PMID:11404483, PMID:16242037, PMID:19221193]. In human cells MOB1A likewise localizes to spindle poles, kinetochores, and the midzone and is required for cytokinetic abscission and centrosome control [PMID:19955215, PMID:22454515].","teleology":[{"year":1998,"claim":"Established the founding principle that Mob1 is an obligate binding partner and effector of the Dbf2 kinase in late mitosis, answering how Dbf2 executes its cell-cycle function.","evidence":"Two-hybrid, reciprocal in vivo/in vitro binding, and genetic suppression in budding yeast","pmids":["9528782","9436989"],"confidence":"High","gaps":["Did not define the catalytic consequence of binding on Dbf2 activity","Mammalian ortholog function not addressed"]},{"year":2001,"claim":"Defined Mob1's position in the mitotic exit network and showed it is required for an upstream kinase (Cdc15) to phosphorylate and activate Dbf2, establishing Mob1 as a coactivator rather than a passive partner.","evidence":"In vitro kinase reconstitution with phosphoacceptor mutagenesis, genetic epistasis, and localization microscopy in yeast","pmids":["11404483","11378390","11434459"],"confidence":"High","gaps":["Mechanism by which Mob1 enables substrate phosphorylation not structurally resolved","Restricted to yeast MEN"]},{"year":2001,"claim":"Connected mammalian MOB1 to phosphatase regulation, showing it associates with striatin-PP2A complexes and is a PP2A dephosphorylation target near the nuclear membrane.","evidence":"Co-IP, pharmacological PP2A inhibition, and immunofluorescence in murine fibroblasts","pmids":["11319234"],"confidence":"Medium","gaps":["Functional consequence of PP2A association unresolved","Single lab, no reciprocal kinase counterpart identified"]},{"year":2003,"claim":"Provided the structural basis for MOB1 function, revealing a zinc-stabilized four-helix bundle with a conserved acidic surface predicted to bind basic kinase regions.","evidence":"X-ray crystallography of human MOB1A with mapping to yeast conditional alleles, corroborated by Xenopus NMR with NDR peptide perturbation","pmids":["12962634","15001360"],"confidence":"High","gaps":["Full-length autoinhibitory elements not yet captured","Did not show phosphorylation-dependent conformational change"]},{"year":2005,"claim":"Defined the intrinsic substrate specificity of the Dbf2-Mob1 kinase complex as an RXXS consensus, allowing prediction of physiological substrates.","evidence":"Peptide library selection and proteome microarray phosphorylation screening","pmids":["16242037"],"confidence":"High","gaps":["In vitro specificity not directly tied to in vivo substrate set","Yeast complex only"]},{"year":2006,"claim":"Showed human MOB1 activates LATS1 only upon membrane targeting and identified a conserved MOB1-binding motif in LATS1, linking MOB1 to the mammalian Hippo effector kinase.","evidence":"Membrane-targeting co-expression, kinase assays, and mutagenesis in cells","pmids":["16674920"],"confidence":"Medium","gaps":["Physiological membrane recruitment trigger unclear","Single lab"]},{"year":2008,"claim":"Identified MST2 phosphorylation of MOB1 at Thr74 as the event nucleating a MOB1-MST2-NDR1 scaffold required for NDR1 activation, establishing a phospho-dependent assembly mechanism in mammals.","evidence":"In vitro kinase assay, T74A mutagenesis, co-IP, and RNAi with NDR1 activity readout","pmids":["18362890"],"confidence":"High","gaps":["Structural basis of the scaffold not resolved at this stage","Relationship to LATS branch not addressed"]},{"year":2009,"claim":"Identified Cdc14 as a direct Dbf2-Mob1 substrate, showing phosphorylation adjacent to its NLS drives nucleolar-to-cytoplasmic relocalization, mechanistically linking the complex to mitotic exit.","evidence":"In vitro kinase assay, MS phosphosite mapping, and NLS localization assays in yeast","pmids":["19221193"],"confidence":"High","gaps":["Mammalian substrate equivalents not defined here"]},{"year":2009,"claim":"Mapped human MOB1 to mitotic structures and showed its recruitment depends on the CPC and Plk1, implicating it in chromosomal passenger relocalization and cytokinesis.","evidence":"Immunofluorescence, RNAi, and live-cell imaging in human cells","pmids":["19955215"],"confidence":"Medium","gaps":["Kinase partner driving midzone function not pinpointed","Single lab"]},{"year":2010,"claim":"Established that among seven MOB family members only MOB1A/B bind LATS1/2 and activate LATS-mediated growth suppression, defining MOB1A/B as the LATS-specific coactivators.","evidence":"Co-IP, in vitro binding, kinase assays, and overexpression/shRNA in cancer cells","pmids":["19739119"],"confidence":"Medium","gaps":["In vivo tumor relevance not yet shown","Single lab"]},{"year":2012,"claim":"Demonstrated MOB1A/B are required for cytokinetic abscission and centrosome control, linking the Hippo coactivator to microtubule dynamics in the midbody.","evidence":"RNAi depletion, microtubule stability assays, and live-cell imaging","pmids":["22454515"],"confidence":"Medium","gaps":["Effector kinase responsible for midbody microtubule destabilization not identified","Single lab"]},{"year":2013,"claim":"Identified praja2 as the E3 ligase that ubiquitylates MOB1 for degradation, establishing proteostatic control of Hippo signaling output relevant to tumor growth.","evidence":"Co-IP, ubiquitylation assay, proteasome inhibition, and in vivo glioblastoma growth","pmids":["23652010"],"confidence":"High","gaps":["Counter-regulatory stabilizing mechanisms not yet defined","Single lab"]},{"year":2015,"claim":"Resolved the phosphorylation-driven activation cycle in atomic detail, showing MOB1 binds autophosphorylated MST2 docking motifs, becomes phosphorylated, and then engages LATS1 via dynamic scaffolding and allostery.","evidence":"Crystal structures of phospho-MST2-MOB1 and phospho-MOB1-LATS1 complexes with biochemical reconstitution","pmids":["26108669"],"confidence":"High","gaps":["Precise autoinhibitory release step not yet captured in full-length structure"]},{"year":2015,"claim":"Showed in vivo that MOB1A/B are the critical Hippo hub upstream of YAP1/TAZ, since their liver-specific loss causes YAP1-dependent tumorigenesis.","evidence":"Conditional double-knockout mice with Yap1 epistatic rescue and cell assays","pmids":["26699479"],"confidence":"High","gaps":["Relative roles of MOB1A vs MOB1B not dissected"]},{"year":2016,"claim":"Captured the autoinhibited full-length MOB1 conformation and showed MST-mediated Thr12/Thr35 phosphorylation relieves a Switch-helix block on the LATS-binding surface via a pull-the-string mechanism.","evidence":"Crystal structures of autoinhibited MOB1B and its complex with LATS1 NTR plus biochemical validation","pmids":["27335147"],"confidence":"High","gaps":["Single lab; in vivo requirement of the Switch helix not tested in mammals"]},{"year":2017,"claim":"Defined how phosphorylation differentially partitions MOB1's two interaction surfaces and expanded its interactome beyond core Hippo kinases to PP6 and DOCK6-8 complexes.","evidence":"Crystal structures, peptide arrays, biophysical binding, and interaction proteomics","pmids":["28373298","28373297"],"confidence":"High","gaps":["Functional roles of PP6 and DOCK associations not characterized"]},{"year":2017,"claim":"Genetically dissected which MOB1 kinase interaction is essential, showing MOB1-LATS/Warts binding underlies tumor suppression while stable MOB1-MST binding is dispensable.","evidence":"Crystal structure of MOB1/NDR2, selective loss-of-interaction variants, Drosophila genetics, and human cells","pmids":["28947795"],"confidence":"High","gaps":["How transient MST binding still contributes catalytically not fully reconciled"]},{"year":2019,"claim":"Identified upstream regulators of MOB1 turnover and activity (Kindlin-2 enhancing praja2-mediated degradation; PR55α/PP2A inhibiting MOB1-driven LATS autoactivation), linking MOB1 control to fibrosis and cancer.","evidence":"Co-IP, ubiquitylation and kinase assays, RNAi, and mouse disease models","pmids":["31825843","31659153"],"confidence":"Medium","gaps":["Single labs; direct vs indirect effects on MOB1 not fully separated"]},{"year":2018,"claim":"Established GSK3β phosphorylation of MOB1 at Ser146 as a degradation signal under PTEN-PI3K-AKT control, connecting MOB1 stability to neurite outgrowth.","evidence":"In vitro kinase assay, S146 mutagenesis, proteasome assays, and in vivo silencing","pmids":["30069702"],"confidence":"Medium","gaps":["Single lab; relationship to praja2 pathway not integrated"]},{"year":2020,"claim":"Revealed that a bacterial effector kinase LegK7 hijacks MOB1A as both substrate and allosteric activator, with the MOB1A N-terminal extension acting as a YAP1 docking platform, generalizing MOB1's coactivator role.","evidence":"Crystal structure of LegK7-MOB1A, kinase assays, interface mutagenesis, and cell-based phosphorylation","pmids":["32513747"],"confidence":"High","gaps":["Whether the same NTE docking operates with host kinases not established"]},{"year":2022,"claim":"Identified competing stabilizing modifications and non-canonical inputs to MOB1: CBP/HDAC6-controlled Lys11 acetylation blocks praja2 ubiquitylation and stabilizes MOB1, while a CAF-exosomal lncRNA scaffolds MOB1A-praja2 to promote its degradation.","evidence":"Acetylation/ubiquitylation assays, K11R mutagenesis, RNA-protein interaction, and in vivo tumor models","pmids":["35349706","36123327"],"confidence":"High","gaps":["Integration of acetylation, phosphorylation, and ubiquitylation timing not resolved"]},{"year":2021,"claim":"Showed EGFR drives tyrosine phosphorylation of MOB1 to inactivate LATS1/2 independently of MST1/2 and activate YAP/TAZ, revealing a receptor-driven, MST-independent branch of MOB1 regulation.","evidence":"Phosphorylation assays, erlotinib inhibition, RNAi, and transcriptomics in HNSCC cells","pmids":["34725466"],"confidence":"Medium","gaps":["Tyrosine phosphosite and direct vs 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Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/15315164","citation_count":6,"is_preprint":false},{"pmid":"12353928","id":"PMC_12353928","title":"MOB-1 and TNF-alpha interact to induce microvascular lung injury.","date":"2002","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/12353928","citation_count":6,"is_preprint":false},{"pmid":"31125466","id":"PMC_31125466","title":"MOB1 regulates thymocyte egress and T-cell survival in mice in a YAP1-independent manner.","date":"2019","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/31125466","citation_count":4,"is_preprint":false},{"pmid":"32943885","id":"PMC_32943885","title":"MOB1 Inhibits Malignant Progression of Colorectal Cancer by Targeting PAK2.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32943885","citation_count":3,"is_preprint":false},{"pmid":"12617835","id":"PMC_12617835","title":"Expression of mOb1, a novel atypical 73 amino acid K50-homeodomain protein, during mouse development.","date":"2002","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/12617835","citation_count":3,"is_preprint":false},{"pmid":"34943148","id":"PMC_34943148","title":"Characterization of a MOB1 Homolog in the Apicomplexan Parasite Toxoplasma gondii.","date":"2021","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34943148","citation_count":3,"is_preprint":false},{"pmid":"40258148","id":"PMC_40258148","title":"MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40258148","citation_count":2,"is_preprint":false},{"pmid":"14516659","id":"PMC_14516659","title":"Expression of mOb1, a novel atypical 73 amino acid K50-homeodomain protein, during mouse development.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/14516659","citation_count":2,"is_preprint":false},{"pmid":"19247963","id":"PMC_19247963","title":"The mob as tumor suppressor (mats1) gene is required for growth control in developing zebrafish embryos.","date":"2009","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19247963","citation_count":2,"is_preprint":false},{"pmid":"40385371","id":"PMC_40385371","title":"Characterization of temperature-sensitive alleles of the septation initiation network protein Mob1 in Schizosaccharomyces pombe.","date":"2025","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/40385371","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.28.672911","title":"Microinjected dsRNA triggers a robust RNAi response in  <i>Stentor coeruleus</i>","date":"2025-08-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.28.672911","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.02.657518","title":"A novel tool for labeling intermediary proteins between two non-interacting proteins","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.02.657518","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.01.25330467","title":"Genomic alterations in the YAP/TAZ pathway are associated with stem cell-like castration-resistant prostate cancer","date":"2025-07-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.01.25330467","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.11.24313439","title":"Identification of 16 novel Alzheimer’s disease susceptibility loci using multi-ancestry meta-analyses of clinical Alzheimer’s disease and AD-by-proxy cases from four whole genome sequencing datasets","date":"2024-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.11.24313439","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35769,"output_tokens":7215,"usd":0.107766,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16356,"output_tokens":6230,"usd":0.118765,"stage2_stop_reason":"end_turn"},"total_usd":0.226531,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"MOB1 (yeast) physically binds DBF2 in vivo and in vitro in the absence of other yeast proteins; this interaction is required for the late mitotic function of DBF2, as temperature-sensitive MOB1 mutants that cannot bind DBF2 fail to execute the telophase/G1 transition. Overexpression of MOB1 suppresses lethality of dbf2Δ dbf20Δ double deletion, indicating DBF2 acts through MOB1.\",\n      \"method\": \"Two-hybrid screen, co-immunoprecipitation, in vitro binding, genetic suppression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vivo and in vitro binding plus multiple genetic epistasis experiments in a single focused study\",\n      \"pmids\": [\"9528782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast MOB1 is a phosphoprotein in vivo and a substrate for the Mps1p kinase in vitro; loss-of-function mob1 alleles cause late nuclear division arrest, and MOB1 shows genetic interactions with LTE1, CDC5, and CDC15, placing it in the mitotic exit pathway.\",\n      \"method\": \"Two-hybrid screen, in vitro kinase assay, conditional allele analysis, genetic interaction\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay plus multiple genetic interactions, foundational paper replicated by subsequent work\",\n      \"pmids\": [\"9436989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Cdc15 kinase activates the Dbf2-Mob1 complex in vitro only when Dbf2 is bound to Mob1; Cdc15 phosphorylates conserved sites Ser-374 and Thr-544 on Dbf2, and Mob1 enables Cdc15 to phosphorylate these critical sites. Dbf2 kinase activity in vivo depends on Tem1, Cdc15, and Mob1.\",\n      \"method\": \"In vitro kinase reconstitution, site-directed mutagenesis, in vivo activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis of phosphoacceptor sites, validated in vivo\",\n      \"pmids\": [\"11404483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Genetic epistasis in budding yeast places Tem1 upstream of Cdc15, which functions upstream of Mob1 and Dbf2 in the mitotic exit network; Dbf2 kinase activity and actin ring formation at the bud neck are both controlled by the same MEN components including Mob1.\",\n      \"method\": \"Genetic epistasis, Dbf2 kinase activity assays, actin ring visualization\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic epistasis with kinase readout, replicated ordering consistent with prior reconstitution data\",\n      \"pmids\": [\"11378390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Mammalian MOB1 (mMOB1) associates with striatin/SG2NA-PP2A complexes; PP2A dephosphorylates mMOB1 since PP2A inhibition with okadaic acid induces serine phosphorylation of PP2A-associated mMOB1. mMOB1 localizes adjacent to the nuclear membrane in murine fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological PP2A inhibition, indirect immunofluorescence, mass spectrometry identification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and pharmacological modulation, single lab\",\n      \"pmids\": [\"11319234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Dbf2 and Mob1 (yeast) localize to spindle pole bodies in anaphase and then relocalize to the bud neck just prior to actin ring assembly; bud-neck localization but not SPB localization of Dbf2 is inhibited by the Bub2 spindle checkpoint, and neck localization of both Dbf2 and Mob1 depends on Cdc14 activity.\",\n      \"method\": \"Fluorescence microscopy of tagged proteins, genetic analysis with checkpoint and cdc14 mutants\",\n      \"journal\": \"Genes & genetic systems\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional epistasis to checkpoint and phosphatase, single lab\",\n      \"pmids\": [\"11434459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of human MOB1A reveals a four-helix bundle stabilized by a bound zinc atom; the N-terminal helix and adjacent elements form an evolutionarily conserved surface with strong negative electrostatic potential that is targeted by temperature-sensitive yeast MOB1 alleles, suggesting this surface mediates electrostatic interactions with basic regions of kinase partners.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation via yeast conditional alleles, and structure corroborated by NMR study (PMID 15001360)\",\n      \"pmids\": [\"12962634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NMR solution structure of Xenopus Mob1 shows a four-helix bundle with a zinc-binding site; chemical shift perturbations upon addition of a peptide from the N-terminal regulatory domain of NDR kinase map the NDR-binding interface to the conserved acidic surface of Mob1, confirming this surface mediates kinase interaction.\",\n      \"method\": \"Heteronuclear multidimensional NMR, chemical shift perturbation mapping\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with direct binding interface mapping, orthogonal to crystal structure data\",\n      \"pmids\": [\"15001360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The Dbf2-Mob1 kinase complex preferentially phosphorylates substrates containing an RXXS motif (serine over threonine required; arginine at -3 position essential and cannot be substituted by lysine), as determined by peptide library selection and proteome chip screening.\",\n      \"method\": \"Peptide library selection, phosphorylation of optimal peptide variants, proteome microarray\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical substrate specificity defined by multiple orthogonal methods (peptide library + proteome chip)\",\n      \"pmids\": [\"16242037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human MOB1 activates LATS1 kinase when membrane-targeted (but not when merely co-expressed); activation requires intact phosphorylation sites in LATS1's activation segment and hydrophobic motif, and occurs within minutes of membrane association. A conserved MOB1-binding motif within LATS1 was identified.\",\n      \"method\": \"Co-expression with membrane-targeting constructs, kinase activity assays, site-directed mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay with mutagenesis and membrane-targeting manipulation, single lab\",\n      \"pmids\": [\"16674920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of S. cerevisiae Mob1 (full-length, 2.0 Å) reveals N-terminal structural elements (helix H0, strand S0, strand S-1); H0 mediates intermolecular homodimerization and S0 binds intramolecularly across the Dbf2-binding site. In vivo functional analysis shows Mob1 mutants targeting H0 or its binding site are biologically compromised.\",\n      \"method\": \"X-ray crystallography, in vivo yeast functional analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with in vivo functional validation of specific structural elements, single lab\",\n      \"pmids\": [\"16934835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MST2 phosphorylates MOB1 at Thr74 in vitro; phosphorylation at Thr74 (but not Thr181) is essential for the formation of a MOB1-MST2-NDR1 scaffold complex and for full NDR1 activation. MOB1-T74A fails to enhance its interaction with NDR1 upon okadaic acid treatment. Knockdown of MOB1 or MST2 abolishes NDR1 activation in cells.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, RNAi knockdown, NDR1 kinase activity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis plus cell-based epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"18362890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Dbf2-Mob1 kinase complex directly phosphorylates Cdc14 phosphatase on serine and threonine residues adjacent to its nuclear localization signal (NLS), thereby abrogating NLS activity and promoting Cdc14 relocalization from the nucleolus to the cytoplasm during mitotic exit.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry phosphorylation site mapping, nuclear localization assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus MS identification of sites plus functional NLS assay, single lab\",\n      \"pmids\": [\"19221193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human Mob1 localizes to spindle poles and kinetochores in early mitosis and to the spindle midzone during cytokinesis; chromosomal passenger complex (CPC) disruption abolishes Mob1 recruitment to kinetochores (but not spindle poles), while Plk1 depletion eliminates spindle-pole Mob1. Mob1 depletion delays CPC and MKLP2 relocalization to the spindle midzone in early anaphase.\",\n      \"method\": \"Immunofluorescence, RNAi depletion, live-cell imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional epistasis to CPC and Plk1, single lab\",\n      \"pmids\": [\"19955215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human Mob1A and Mob1B are required for cytokinetic abscission; RNAi depletion causes abscission failure due to hyper-stabilization of microtubules in the midbody region. Mob1 depletion also increases cell motility and induces prolonged centriole separation in G1; conversely, Mob1A or Mob1B overexpression prevents centrosome splitting.\",\n      \"method\": \"RNAi depletion, microtubule stability assay, live-cell imaging, cytokinesis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with specific cellular phenotype and mechanistic readout (microtubule stability), single lab\",\n      \"pmids\": [\"22454515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The RING E3 ubiquitin ligase praja2 ubiquitylates and targets MOB1 for proteasomal degradation; this degradation attenuates LATS/NDR kinase activity and the Hippo tumor-suppressor cascade, sustaining glioblastoma growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, proteasome inhibition, in vivo tumor growth\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, ubiquitylation assay, and in vivo rescue, single lab but multiple methods\",\n      \"pmids\": [\"23652010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human MOB1 binds autophosphorylated docking motifs in active MST2, enabling MOB1 phosphorylation by MST2; phosphorylated MOB1 undergoes conformational activation and binds LATS1. Crystal structures of phospho-MST2-MOB1 and phospho-MOB1-LATS1 complexes reveal phosphorylation-dependent binding events. MOB1 mediates LATS1 activation through dynamic scaffolding and allosteric mechanisms.\",\n      \"method\": \"Biochemical binding assays, in vitro kinase assays, X-ray crystallography, functional epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with biochemical reconstitution and mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26108669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mob1a/Mob1b double knockout in mouse liver causes hyperproliferation, hepatocyte dedifferentiation, enhanced epithelial-mesenchymal transition, and development of liver cancers; these phenotypes are strongly dependent on YAP1 and partially on TAZ and TGF-β2/3 signaling, placing MOB1A/B as the critical hub of Hippo signaling upstream of LATS-YAP1/TAZ.\",\n      \"method\": \"Conditional knockout mice, genetic epistasis (Yap1 rescue), drug screening, cell culture assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse KO with YAP1-dependent epistasis rescue, multiple cellular phenotypes assessed\",\n      \"pmids\": [\"26699479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of full-length MOB1B reveals an autoinhibited conformation where the N-terminal Switch helix (stabilized by SN strand β-sheet formation) blocks the LATS1-binding surface. MST1/2-mediated phosphorylation of Thr12 and Thr35 structurally relieves autoinhibition via a 'pull-the-string' mechanism, enabling LATS1 binding.\",\n      \"method\": \"X-ray crystallography of full-length MOB1B, complex with LATS1 NTR, biochemical validation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of autoinhibited and complex forms with mechanistic explanation, single lab\",\n      \"pmids\": [\"27335147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MOB1A phosphopeptide-binding specificity is highly complementary to MST1/2 substrate phosphorylation consensus; autophosphorylation of MST1/2 on multiple threonine residues provides several MOB1A-binding sites with varying affinities. Crystal structures of MOB1A with two MST1 phosphopeptides define the phosphopeptide-binding consensus. Phosphopeptide-binding is conserved in six of seven human MOB family members.\",\n      \"method\": \"Proteomics, peptide arrays, biochemical binding assays, X-ray crystallography, interaction proteomics\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including crystal structures, peptide arrays, and proteomics in one study\",\n      \"pmids\": [\"28373298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MOB1 phosphorylation by upstream MST kinases differentially regulates its two protein interaction surfaces: phosphorylation promotes binding to MST via the phosphopeptide-binding surface while modulating LATS/NDR binding at a distinct surface. MOB1A also associates in a phosphorylation-dependent manner with PP6 phosphatase and Rho guanine exchange factor complexes (DOCK6-8) through mechanisms distinct from MST1/2 binding.\",\n      \"method\": \"Biochemical assays, biophysical binding measurements, mutagenesis, structural analysis, interaction proteomics\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — comprehensive biochemical, biophysical, mutational and structural analyses with proteomics validation\",\n      \"pmids\": [\"28373297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MOB1/Warts (LATS) binding is essential for tumor suppression, tissue growth control, and development in Drosophila and human cells, while stable MOB1/Hippo (MST) binding is dispensable and MOB1/Trc (NDR) binding alone is insufficient. Crystal structure of the MOB1/NDR2 complex defines key residues for differential binding to Hippo core kinases.\",\n      \"method\": \"Crystal structure, mutagenesis, Drosophila genetic analysis, human cancer cell studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with selective loss-of-interaction variants validated in multiple model systems\",\n      \"pmids\": [\"28947795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kindlin-2 (focal adhesion molecule) interacts with MOB1 and promotes its degradation by enhancing MOB1-praja2 (E3 ligase) interaction; this inhibits LATS1 phosphorylation and YAP phosphorylation, promoting YAP nuclear translocation. Kindlin-2 depletion activates Hippo/YAP signaling and alleviates renal fibrosis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, MOB1 degradation assay, mouse knockout with UUO model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with functional degradation assay and in vivo rescue, single lab\",\n      \"pmids\": [\"31825843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PR55α regulatory subunit of PP2A inhibits MOB1-triggered autoactivation of LATS1/2 kinases, thereby promoting YAP activation; PR55α also directly interacts with YAP. This identifies a PP2A-MOB1-LATS1/2 axis controlling YAP in pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, RNAi knockdown, anchorage-independent growth assay\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase activity assay with co-IP and RNAi, single lab\",\n      \"pmids\": [\"31659153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MOB1 stability is regulated by the PTEN-GSK3β axis; GSK3β phosphorylates MOB1 on Ser146, targeting it for ubiquitin-proteasome degradation. PTEN knockdown (via PI3K-AKT) suppresses GSK3β and stabilizes MOB1 protein, promoting neurite outgrowth.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, ubiquitin-proteasome assay, lentiviral in vivo silencing\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis and proteasome assay, single lab\",\n      \"pmids\": [\"30069702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The Legionella pneumophila effector kinase LegK7 uses MOB1A as both a substrate and an allosteric activator; MOB1A binding to the LegK7 kinase domain reorients the two kinase lobes into an ATP-binding-compatible closed conformation. The MOB1A N-terminal extension (NTE) serves as a docking site for downstream substrates (YAP1). Crystal structure of the LegK7-MOB1A complex was determined.\",\n      \"method\": \"X-ray crystallography, in vitro kinase assay, mutagenesis of interface residues, cell-based phosphorylation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and in vitro/cell-based validation of allosteric mechanism\",\n      \"pmids\": [\"32513747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGFR promotes tyrosine phosphorylation of MOB1 (a core Hippo component) and inactivates LATS1/2 independently of MST1/2, thereby activating YAP/TAZ in head and neck squamous cell carcinoma cells.\",\n      \"method\": \"Phosphorylation assays, kinase inhibition (erlotinib), RNAi and loss-of-function experiments, transcriptomic analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation assays with inhibitor and RNAi epistasis, single lab\",\n      \"pmids\": [\"34725466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MOB1 is acetylated at Lys11 by acetyltransferase CBP and deacetylated by HDAC6; MOB1-K11 acetylation stabilizes MOB1 by reducing its binding to E3 ligase Praja2 and subsequent ubiquitination, and also increases MOB1 phosphorylation and activates LATS1. Oxidative stress promotes MOB1 acetylation by suppressing CBP degradation, independently of MST1/2 kinase activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, in vitro acetylation assay, site-directed mutagenesis (K11R), in vitro and in vivo tumor assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical acetylation/ubiquitylation assays with mutagenesis and functional in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"35349706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The lncRNA WEE2-AS1 (from CAF-derived exosomes) functions as a scaffold bridging MOB1A and E3 ligase praja2, leading to MOB1A ubiquitin-proteasome degradation, Hippo pathway inhibition, and increased YAP nuclear translocation in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, RNA-protein interaction assay, ubiquitylation assay, in vivo tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitylation assay with in vivo validation, single lab\",\n      \"pmids\": [\"36123327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Among all seven human MOB family members, only hMOB1A and hMOB1B interact with both LATS1 and LATS2 in vitro and in vivo; overexpression of hMOB1 in cancer cells activates LATS kinase activity and inhibits proliferation or causes apoptosis, with membrane-targeted hMOB1 producing stronger effects.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding, kinase activity assay, overexpression and shRNA knockdown in cancer cells\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with kinase activity assay, comprehensive comparison of MOB family members, single lab\",\n      \"pmids\": [\"19739119\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MOB1A is a conserved scaffold/adaptor protein and core component of the Hippo tumor-suppressor pathway that functions by: (1) binding autophosphorylated MST1/2 kinases via a phosphopeptide-recognition surface, relieving its own autoinhibition upon MST-mediated phosphorylation at Thr12/Thr35; (2) allosterically activating LATS1/2 and NDR kinases through a distinct interaction surface, thereby promoting YAP/TAZ phosphorylation and cytoplasmic retention; (3) serving as a substrate for multiple post-translational modifications—phosphorylation by MST1/2 (activating), ubiquitylation by praja2 E3 ligase (destabilizing, counteracted by acetylation at K11 by CBP/deacetylation by HDAC6, and by phosphorylation by GSK3β at Ser146)—that collectively tune its abundance and activity; and (4) directly activating NDR/LATS-family kinases (orthologous to yeast Dbf2) in the mitotic exit network to phosphorylate substrates (e.g., Cdc14/NLS) and regulate cytokinesis, with MOB1-LATS/Warts binding being the interaction essential for tumor suppression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MOB1A is a conserved kinase coactivator and phosphorylation-controlled scaffold that operates as a core hub of the Hippo tumor-suppressor pathway and the mitotic exit/cytokinesis machinery [#16, #17]. The protein folds as a zinc-stabilized four-helix bundle whose conserved, electrostatically negative surface engages basic regulatory regions of partner kinases [#6, #7]. In the activation cycle, autophosphorylated MST1/2 present docking phosphomotifs that MOB1A recognizes through a dedicated phosphopeptide-binding surface, and MST-mediated phosphorylation of MOB1A (e.g. Thr12/Thr35) relieves an N-terminal Switch-helix autoinhibition by a 'pull-the-string' mechanism, exposing a distinct surface for LATS/NDR kinase binding [#16, #18, #19]; through dynamic scaffolding and allostery MOB1A then activates LATS1/2 and NDR kinases [#9, #11, #16]. The MOB1-LATS(Warts) interaction is the binding event essential for tumor suppression and growth control, whereas stable MOB1-MST binding is dispensable and MOB1-NDR binding alone is insufficient [#21]. Genetically, MOB1A/B act as the critical node upstream of LATS-YAP1/TAZ, since their loss in mouse liver drives YAP1-dependent hyperproliferation, dedifferentiation, EMT, and tumorigenesis [#17]. MOB1A abundance is tuned by competing post-translational modifications: praja2-mediated ubiquitylation drives proteasomal degradation [#15], opposed by CBP/HDAC6-controlled Lys11 acetylation that blocks praja2 binding and stabilizes the protein [#27], while GSK3β phosphorylation at Ser146 promotes its degradation [#24]. This conserved coactivator role originated in the yeast mitotic exit network, where Mob1 binds and activates the Dbf2 kinase—itself activated by Cdc15 downstream of Tem1—and the Dbf2-Mob1 complex phosphorylates RXXS-motif substrates including Cdc14 to control nucleolar release and cytokinesis [#0, #2, #8, #12]. In human cells MOB1A likewise localizes to spindle poles, kinetochores, and the midzone and is required for cytokinetic abscission and centrosome control [#13, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the founding principle that Mob1 is an obligate binding partner and effector of the Dbf2 kinase in late mitosis, answering how Dbf2 executes its cell-cycle function.\",\n      \"evidence\": \"Two-hybrid, reciprocal in vivo/in vitro binding, and genetic suppression in budding yeast\",\n      \"pmids\": [\"9528782\", \"9436989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the catalytic consequence of binding on Dbf2 activity\", \"Mammalian ortholog function not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined Mob1's position in the mitotic exit network and showed it is required for an upstream kinase (Cdc15) to phosphorylate and activate Dbf2, establishing Mob1 as a coactivator rather than a passive partner.\",\n      \"evidence\": \"In vitro kinase reconstitution with phosphoacceptor mutagenesis, genetic epistasis, and localization microscopy in yeast\",\n      \"pmids\": [\"11404483\", \"11378390\", \"11434459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Mob1 enables substrate phosphorylation not structurally resolved\", \"Restricted to yeast MEN\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected mammalian MOB1 to phosphatase regulation, showing it associates with striatin-PP2A complexes and is a PP2A dephosphorylation target near the nuclear membrane.\",\n      \"evidence\": \"Co-IP, pharmacological PP2A inhibition, and immunofluorescence in murine fibroblasts\",\n      \"pmids\": [\"11319234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PP2A association unresolved\", \"Single lab, no reciprocal kinase counterpart identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the structural basis for MOB1 function, revealing a zinc-stabilized four-helix bundle with a conserved acidic surface predicted to bind basic kinase regions.\",\n      \"evidence\": \"X-ray crystallography of human MOB1A with mapping to yeast conditional alleles, corroborated by Xenopus NMR with NDR peptide perturbation\",\n      \"pmids\": [\"12962634\", \"15001360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length autoinhibitory elements not yet captured\", \"Did not show phosphorylation-dependent conformational change\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the intrinsic substrate specificity of the Dbf2-Mob1 kinase complex as an RXXS consensus, allowing prediction of physiological substrates.\",\n      \"evidence\": \"Peptide library selection and proteome microarray phosphorylation screening\",\n      \"pmids\": [\"16242037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro specificity not directly tied to in vivo substrate set\", \"Yeast complex only\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed human MOB1 activates LATS1 only upon membrane targeting and identified a conserved MOB1-binding motif in LATS1, linking MOB1 to the mammalian Hippo effector kinase.\",\n      \"evidence\": \"Membrane-targeting co-expression, kinase assays, and mutagenesis in cells\",\n      \"pmids\": [\"16674920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological membrane recruitment trigger unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified MST2 phosphorylation of MOB1 at Thr74 as the event nucleating a MOB1-MST2-NDR1 scaffold required for NDR1 activation, establishing a phospho-dependent assembly mechanism in mammals.\",\n      \"evidence\": \"In vitro kinase assay, T74A mutagenesis, co-IP, and RNAi with NDR1 activity readout\",\n      \"pmids\": [\"18362890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the scaffold not resolved at this stage\", \"Relationship to LATS branch not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified Cdc14 as a direct Dbf2-Mob1 substrate, showing phosphorylation adjacent to its NLS drives nucleolar-to-cytoplasmic relocalization, mechanistically linking the complex to mitotic exit.\",\n      \"evidence\": \"In vitro kinase assay, MS phosphosite mapping, and NLS localization assays in yeast\",\n      \"pmids\": [\"19221193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian substrate equivalents not defined here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped human MOB1 to mitotic structures and showed its recruitment depends on the CPC and Plk1, implicating it in chromosomal passenger relocalization and cytokinesis.\",\n      \"evidence\": \"Immunofluorescence, RNAi, and live-cell imaging in human cells\",\n      \"pmids\": [\"19955215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase partner driving midzone function not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that among seven MOB family members only MOB1A/B bind LATS1/2 and activate LATS-mediated growth suppression, defining MOB1A/B as the LATS-specific coactivators.\",\n      \"evidence\": \"Co-IP, in vitro binding, kinase assays, and overexpression/shRNA in cancer cells\",\n      \"pmids\": [\"19739119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo tumor relevance not yet shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated MOB1A/B are required for cytokinetic abscission and centrosome control, linking the Hippo coactivator to microtubule dynamics in the midbody.\",\n      \"evidence\": \"RNAi depletion, microtubule stability assays, and live-cell imaging\",\n      \"pmids\": [\"22454515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector kinase responsible for midbody microtubule destabilization not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified praja2 as the E3 ligase that ubiquitylates MOB1 for degradation, establishing proteostatic control of Hippo signaling output relevant to tumor growth.\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, proteasome inhibition, and in vivo glioblastoma growth\",\n      \"pmids\": [\"23652010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Counter-regulatory stabilizing mechanisms not yet defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the phosphorylation-driven activation cycle in atomic detail, showing MOB1 binds autophosphorylated MST2 docking motifs, becomes phosphorylated, and then engages LATS1 via dynamic scaffolding and allostery.\",\n      \"evidence\": \"Crystal structures of phospho-MST2-MOB1 and phospho-MOB1-LATS1 complexes with biochemical reconstitution\",\n      \"pmids\": [\"26108669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise autoinhibitory release step not yet captured in full-length structure\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed in vivo that MOB1A/B are the critical Hippo hub upstream of YAP1/TAZ, since their liver-specific loss causes YAP1-dependent tumorigenesis.\",\n      \"evidence\": \"Conditional double-knockout mice with Yap1 epistatic rescue and cell assays\",\n      \"pmids\": [\"26699479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative roles of MOB1A vs MOB1B not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Captured the autoinhibited full-length MOB1 conformation and showed MST-mediated Thr12/Thr35 phosphorylation relieves a Switch-helix block on the LATS-binding surface via a pull-the-string mechanism.\",\n      \"evidence\": \"Crystal structures of autoinhibited MOB1B and its complex with LATS1 NTR plus biochemical validation\",\n      \"pmids\": [\"27335147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab; in vivo requirement of the Switch helix not tested in mammals\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined how phosphorylation differentially partitions MOB1's two interaction surfaces and expanded its interactome beyond core Hippo kinases to PP6 and DOCK6-8 complexes.\",\n      \"evidence\": \"Crystal structures, peptide arrays, biophysical binding, and interaction proteomics\",\n      \"pmids\": [\"28373298\", \"28373297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional roles of PP6 and DOCK associations not characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetically dissected which MOB1 kinase interaction is essential, showing MOB1-LATS/Warts binding underlies tumor suppression while stable MOB1-MST binding is dispensable.\",\n      \"evidence\": \"Crystal structure of MOB1/NDR2, selective loss-of-interaction variants, Drosophila genetics, and human cells\",\n      \"pmids\": [\"28947795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transient MST binding still contributes catalytically not fully reconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified upstream regulators of MOB1 turnover and activity (Kindlin-2 enhancing praja2-mediated degradation; PR55α/PP2A inhibiting MOB1-driven LATS autoactivation), linking MOB1 control to fibrosis and cancer.\",\n      \"evidence\": \"Co-IP, ubiquitylation and kinase assays, RNAi, and mouse disease models\",\n      \"pmids\": [\"31825843\", \"31659153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs; direct vs indirect effects on MOB1 not fully separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established GSK3β phosphorylation of MOB1 at Ser146 as a degradation signal under PTEN-PI3K-AKT control, connecting MOB1 stability to neurite outgrowth.\",\n      \"evidence\": \"In vitro kinase assay, S146 mutagenesis, proteasome assays, and in vivo silencing\",\n      \"pmids\": [\"30069702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; relationship to praja2 pathway not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that a bacterial effector kinase LegK7 hijacks MOB1A as both substrate and allosteric activator, with the MOB1A N-terminal extension acting as a YAP1 docking platform, generalizing MOB1's coactivator role.\",\n      \"evidence\": \"Crystal structure of LegK7-MOB1A, kinase assays, interface mutagenesis, and cell-based phosphorylation\",\n      \"pmids\": [\"32513747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same NTE docking operates with host kinases not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified competing stabilizing modifications and non-canonical inputs to MOB1: CBP/HDAC6-controlled Lys11 acetylation blocks praja2 ubiquitylation and stabilizes MOB1, while a CAF-exosomal lncRNA scaffolds MOB1A-praja2 to promote its degradation.\",\n      \"evidence\": \"Acetylation/ubiquitylation assays, K11R mutagenesis, RNA-protein interaction, and in vivo tumor models\",\n      \"pmids\": [\"35349706\", \"36123327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of acetylation, phosphorylation, and ubiquitylation timing not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed EGFR drives tyrosine phosphorylation of MOB1 to inactivate LATS1/2 independently of MST1/2 and activate YAP/TAZ, revealing a receptor-driven, MST-independent branch of MOB1 regulation.\",\n      \"evidence\": \"Phosphorylation assays, erlotinib inhibition, RNAi, and transcriptomics in HNSCC cells\",\n      \"pmids\": [\"34725466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tyrosine phosphosite and direct vs indirect mechanism not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple PTMs (MST/GSK3β/EGFR phosphorylation, K11 acetylation, praja2 ubiquitylation) are temporally and spatially integrated to set MOB1A levels and direct it between Hippo signaling and mitotic exit remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating competing modifications\", \"Mammalian MOB1A vs MOB1B functional division undefined\", \"Physiological cytokinesis substrates of human MOB1 not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 9, 11, 16, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 16, 19]},\n      {\"term_id\": \"GO:0019904\", \"supporting_discovery_ids\": [16, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [5, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 17, 21]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 24, 27]}\n    ],\n    \"complexes\": [\n      \"Dbf2-Mob1 complex\",\n      \"MST2-MOB1-NDR1 scaffold\",\n      \"MOB1-LATS1/2 complex\",\n      \"striatin/SG2NA-PP2A complex\"\n    ],\n    \"partners\": [\n      \"MST1\",\n      \"MST2\",\n      \"LATS1\",\n      \"LATS2\",\n      \"NDR1\",\n      \"praja2\",\n      \"DBF2\",\n      \"CDC15\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}