{"gene":"MOB2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2001,"finding":"Yeast Cbk1 kinase and its interacting protein Mob2 regulate asymmetric cell fates by activating and localizing the Ace2 transcription factor specifically to the daughter nucleus, thereby inducing daughter-specific gene expression programs including genes for cell wall degradation and cell separation.","method":"Genetic analysis, epistasis, localization studies, ectopic expression of Ace2","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetics, localization, ectopic expression), highly cited foundational study","pmids":["11747810"],"is_preprint":false},{"year":2004,"finding":"The Mob2/Cbk1 pathway acts in parallel with the Ras/PKA pathway to control bud site selection and cell cycle progression in S. cerevisiae; Mob2 functions through proper localization of the Ace2 transcription factor, and the growth/budding defects of mob2Δ strains are suppressed by overexpression of the PKA catalytic subunit Tpk1.","method":"Genetic epistasis, double-mutant analysis, suppressor overexpression","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined phenotypic readouts, single lab","pmids":["14871942"],"is_preprint":false},{"year":2010,"finding":"Human MOB2 (hMOB2) binds to the N-terminal region of NDR1 in a manner distinct from hMOB1A/B: it binds unphosphorylated NDR1, competes with hMOB1A for NDR binding, and acts as a negative regulator of NDR kinase activity. RNAi depletion of hMOB2 increases NDR kinase activity, and hMOB2 overexpression interferes with NDR-dependent death receptor signaling and centrosome overduplication.","method":"Co-immunoprecipitation, RNAi knockdown, kinase activity assays, NDR binding competition assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays, RNAi, kinase assays, functional cellular readouts; multiple orthogonal methods","pmids":["20624913"],"is_preprint":false},{"year":2011,"finding":"In Candida albicans, the CDK Cdc28 phosphorylates Mob2 at four CDK consensus sites upon hyphal induction. Alanine mutations at these sites impair hyphal development, cause enlarged hyphal tips with illicit cell separation, and disrupt polarisome component maintenance at hyphal tips, defining a signaling pathway where Cdc28 controls Cbk1 NDR kinase through regulatory phosphorylation of Mob2.","method":"Site-directed mutagenesis of CDK phosphorylation sites, phenotypic analysis, localization assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — phosphosite mutagenesis combined with functional and localization readouts","pmids":["21593210"],"is_preprint":false},{"year":2011,"finding":"Mouse Mob2 promotes neurite formation in Neuro2A cells; Mob2 knockdown decreases neurite outgrowth and alters actin cytoskeleton rearrangement, reducing phosphorylated Moesin levels, while Mob2 overexpression promotes neurite formation.","method":"RNAi knockdown, overexpression, actin cytoskeleton staining, phospho-Moesin western blot","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, loss- and gain-of-function with cellular readouts but limited mechanistic depth","pmids":["21237165"],"is_preprint":false},{"year":2009,"finding":"Drosophila Mob2 (Dmob2) localizes to the apical membrane and later to the rhabdomere base of photoreceptor cells; RNAi knockdown of Dmob2 impairs rhabdomere formation and disrupts subcellular localization of phosphorylated Moesin and Crumbs in developing photoreceptors.","method":"Immunocytochemistry, RNAi knockdown, localization analysis","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 3 — localization and RNAi with functional consequence, single lab","pmids":["19834743"],"is_preprint":false},{"year":2013,"finding":"Drosophila Mob2 regulates larval neuromuscular junction (NMJ) morphology by functioning as an NDR kinase activator; presynaptic expression of Mob2 is necessary and sufficient for NMJ growth regulation, and Mob2 interacts in a dominant, dose-dependent manner with the NDR kinase Tricornered (but not Warts) to control NMJ development.","method":"Genetic mapping, transformation rescue, dominant genetic interaction analysis, tissue-specific expression","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis, rescue experiments with specific NDR kinase interaction, single lab","pmids":["23979583"],"is_preprint":false},{"year":2018,"finding":"MOB2 knockdown in the developing mouse cortex disrupts neuronal migration and positioning; reduced Mob2 expression increases phosphorylation of Filamin A (an actin cross-linking protein), and cilia positioning and number within migrating neurons is impaired. Reduction of an upstream modulator Dchs1 phenocopies this defect, placing MOB2 downstream of Dchs1 in a pathway controlling neuronal positioning.","method":"In utero knockdown, immunofluorescence, phospho-Filamin A western blot, genetic epistasis with Dchs1","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in vivo with defined molecular readout (Filamin A phosphorylation) and pathway placement","pmids":["29593499"],"is_preprint":false},{"year":2020,"finding":"MOB2 acts as a tumor suppressor in GBM by negatively regulating the FAK/Akt pathway involving integrin signaling; MOB2 also interacts with and promotes PKA signaling in a cAMP-dependent manner, and MOB2 contributes to cAMP/PKA-mediated inactivation of FAK/Akt to suppress GBM cell migration and invasion.","method":"Co-immunoprecipitation, overexpression/knockdown, kinase pathway western blots, xenograft models, pharmacological manipulation (Forskolin, H89)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP for PKA interaction, multiple functional readouts, pharmacological validation, single lab","pmids":["32286266"],"is_preprint":false},{"year":2025,"finding":"Astrocyte-conditional knockout of MOB2 inhibits the conversion of reactive astrocytes from A1 to A2 phenotype after spinal cord injury; mechanistically, MOB2 increases PI3K-AKT signaling activation to promote A1-to-A2 transformation, and the AKT activator sc79 rescues astrocyte subtype conversion and functional recovery in MOB2-CKO mice.","method":"Conditional knockout (GFAP-Cre), primary astrocyte reactive cell model, PI3K-AKT pathway analysis, pharmacological rescue with sc79","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined signaling pathway and pharmacological rescue, single lab","pmids":["39863205"],"is_preprint":false},{"year":2026,"finding":"hMOB2 depletion sensitizes p53-wild-type lung cancer cells (A549) to PARP inhibitors (olaparib, rucaparib) through enhanced p53 phosphorylation, persistent γH2AX accumulation, increased DNA strand breaks, and caspase-3-dependent apoptosis; this sensitization requires functional p53, as it is absent in p53-null cells and restored by p53 re-expression.","method":"siRNA knockdown, clonogenic assays, comet assays, immunofluorescence (γH2AX), caspase-3 activity, p53 reconstitution via retroviral transduction","journal":"Current issues in molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, p53 dependency validated by reconstitution, single lab","pmids":["41899447"],"is_preprint":false}],"current_model":"MOB2 is a regulatory cofactor that negatively modulates NDR kinases (NDR1/2) by competing with the activating MOB1 proteins for NDR N-terminal binding, keeping NDR in an unphosphorylated, less active state; in parallel, MOB2 participates in cAMP/PKA signaling, suppresses FAK/Akt pathway activity, promotes PI3K-AKT-dependent astrocyte phenotype switching, regulates neuronal migration via Filamin A phosphorylation, and in its founding yeast/fungal context, is phosphorylated by CDKs to enable NDR kinase (Cbk1)-dependent localization of the Ace2 transcription factor for asymmetric daughter-cell fate determination."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing MOB2 as an essential NDR kinase cofactor for asymmetric cell-fate determination resolved how daughter-specific transcription is achieved in yeast: Mob2 and Cbk1 cooperate to activate and localize the Ace2 transcription factor exclusively to the daughter nucleus.","evidence":"Genetic epistasis, localization, and ectopic Ace2 expression in S. cerevisiae","pmids":["11747810"],"confidence":"High","gaps":["Biochemical mechanism by which Mob2 activates Cbk1 kinase was not resolved","Whether the Mob2-Cbk1 module has conserved functions in metazoans was unknown"]},{"year":2004,"claim":"Demonstrating that the Mob2/Cbk1 pathway acts in parallel with Ras/PKA signaling for bud site selection expanded MOB2 function beyond Ace2 regulation and established cross-talk with cAMP/PKA signaling.","evidence":"Genetic suppression of mob2Δ by PKA catalytic subunit overexpression in S. cerevisiae","pmids":["14871942"],"confidence":"Medium","gaps":["Physical or biochemical basis of Mob2-PKA cross-talk was not defined","Whether this parallel relationship is conserved in mammalian cells was untested"]},{"year":2009,"claim":"Drosophila Mob2 localization studies in photoreceptors provided the first evidence that MOB2 functions at apical membranes to organize polarity determinants (Crumbs, phospho-Moesin) in a multicellular developmental context.","evidence":"Immunocytochemistry and RNAi knockdown in Drosophila photoreceptors","pmids":["19834743"],"confidence":"Medium","gaps":["Direct binding partners mediating apical targeting were not identified","Whether MOB2 acts through an NDR kinase in this context was not tested"]},{"year":2010,"claim":"Identification of human MOB2 as a negative regulator of NDR kinases — binding unphosphorylated NDR1 and competing with the activator MOB1 — inverted the expected activating role and established a competitive cofactor-switching mechanism for NDR regulation.","evidence":"Co-immunoprecipitation, competition binding assays, RNAi, kinase activity assays in human cells","pmids":["20624913"],"confidence":"High","gaps":["Structural basis for selective binding of MOB2 to unphosphorylated NDR was not determined","In vivo physiological contexts where MOB2-mediated NDR inhibition is critical were unclear"]},{"year":2011,"claim":"CDK-dependent phosphorylation of fungal Mob2 was shown to be required for hyphal morphogenesis, linking cell-cycle kinase signaling to Mob2-Cbk1 pathway output and polarisome maintenance at hyphal tips.","evidence":"CDK phosphosite mutagenesis, phenotypic and localization analysis in C. albicans","pmids":["21593210"],"confidence":"High","gaps":["Whether CDK phosphorylation alters Mob2-Cbk1 binding affinity or Mob2 localization directly was not biochemically resolved","Relevance of analogous phosphorylation events on mammalian MOB2 was unknown"]},{"year":2011,"claim":"Mouse Mob2 was linked to neurite outgrowth and actin cytoskeleton remodeling via phospho-Moesin, providing the first mammalian neuronal function for MOB2.","evidence":"RNAi and overexpression in Neuro2A cells with phospho-Moesin readout","pmids":["21237165"],"confidence":"Medium","gaps":["Whether MOB2 acts through NDR kinases or an independent pathway in neurite formation was not determined","Moesin regulation was correlative; direct mechanism was not established"]},{"year":2013,"claim":"Drosophila genetic analysis demonstrated that Mob2 acts specifically through the NDR kinase Tricornered (not Warts/LATS) to regulate presynaptic NMJ morphology, clarifying NDR-kinase specificity of MOB2 in a neuronal context.","evidence":"Genetic mapping, rescue, and dose-dependent dominant interactions at the Drosophila NMJ","pmids":["23979583"],"confidence":"Medium","gaps":["Whether MOB2 activates or inhibits Tricornered in this context was not biochemically resolved","Downstream substrates of Trc mediating NMJ growth were not identified"]},{"year":2018,"claim":"In vivo cortical knockdown revealed that MOB2 controls neuronal migration and cilia positioning by restraining Filamin A phosphorylation, placing MOB2 downstream of the protocadherin-family protein Dchs1 in a neuronal positioning pathway.","evidence":"In utero electroporation knockdown in mouse cortex, phospho-Filamin A analysis, epistasis with Dchs1","pmids":["29593499"],"confidence":"Medium","gaps":["Kinase responsible for Filamin A hyperphosphorylation upon MOB2 loss was not identified","Whether this pathway involves NDR kinase modulation was not tested"]},{"year":2020,"claim":"MOB2 was established as a tumor-suppressive factor in glioblastoma that physically interacts with PKA and promotes cAMP/PKA-dependent inactivation of the FAK/Akt axis, connecting MOB2 to integrin signaling and cancer cell invasion.","evidence":"Co-IP for PKA, overexpression/knockdown, pharmacological modulation (Forskolin, H89), xenograft models in GBM cells","pmids":["32286266"],"confidence":"Medium","gaps":["Direct binding interface between MOB2 and PKA subunits was not mapped","Relationship between MOB2-PKA and MOB2-NDR functions was not clarified"]},{"year":2025,"claim":"Conditional knockout demonstrated that astrocytic MOB2 activates PI3K-AKT signaling to promote A1-to-A2 reactive astrocyte conversion after spinal cord injury, with pharmacological AKT activation rescuing the phenotype.","evidence":"GFAP-Cre conditional knockout, primary astrocyte models, PI3K-AKT pathway analysis, sc79 rescue in vivo","pmids":["39863205"],"confidence":"Medium","gaps":["Mechanism by which MOB2 activates PI3K-AKT is unknown — whether through NDR inhibition or an independent route","Whether MOB2 loss affects astrocyte-neuron signaling beyond phenotype switching was not explored"]},{"year":2026,"claim":"MOB2 depletion was found to sensitize p53-wild-type lung cancer cells to PARP inhibitors through enhanced p53 phosphorylation and persistent DNA damage, revealing a role for MOB2 in the DNA damage response that depends on functional p53.","evidence":"siRNA knockdown, clonogenic and comet assays, γH2AX immunofluorescence, caspase-3 activity, p53 reconstitution","pmids":["41899447"],"confidence":"Medium","gaps":["Mechanism linking MOB2 to p53 phosphorylation and DNA repair proficiency is unknown","Whether MOB2's NDR-regulatory or PKA-regulatory functions mediate DNA damage sensitivity was not tested"]},{"year":null,"claim":"A unified mechanistic model integrating MOB2's NDR-inhibitory, PKA-stimulatory, and PI3K-AKT-activating functions remains unresolved; whether these represent independent activities or converge through a common scaffolding mechanism is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data exist for MOB2 in complex with any partner","Post-translational regulation of mammalian MOB2 (analogous to CDK phosphorylation in fungi) has not been characterized","Conditional knockout phenotypes in tissues beyond brain and spinal cord have not been reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6,7]}],"complexes":[],"partners":["NDR1","NDR2","CBK1","PRKACA","FLNA","DCHS1"],"other_free_text":[]},"mechanistic_narrative":"MOB2 is a conserved regulatory scaffold that modulates NDR/LATS-family kinase signaling and multiple downstream pathways controlling cell polarity, morphogenesis, and neuronal positioning. In human cells, MOB2 binds the N-terminal region of NDR1/2 kinases in competition with the activating cofactor MOB1, thereby restraining NDR kinase activity and NDR-dependent processes including centrosome duplication and death receptor signaling [PMID:20624913]. Beyond NDR regulation, MOB2 participates in cAMP/PKA-mediated suppression of the FAK/Akt axis to limit glioblastoma cell migration [PMID:32286266], activates PI3K-AKT signaling to promote reactive astrocyte phenotype switching after spinal cord injury [PMID:39863205], and controls cortical neuronal migration through regulation of Filamin A phosphorylation downstream of the protocadherin Dchs1 [PMID:29593499]. In budding yeast and Candida, Mob2 partners with the NDR kinase Cbk1 to direct asymmetric daughter-cell gene expression via the Ace2 transcription factor, and CDK-dependent phosphorylation of Mob2 is essential for hyphal morphogenesis [PMID:11747810, PMID:21593210]."},"prefetch_data":{"uniprot":{"accession":"Q70IA6","full_name":"MOB kinase activator 2","aliases":["HCCA2","Mob2 homolog","Mps one binder kinase activator-like 2"],"length_aa":237,"mass_kda":26.9,"function":"Stimulates the autophosphorylation and kinase activity of STK38 and STK38L","subcellular_location":"Nucleus; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q70IA6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MOB2","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"STK38L","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/MOB2","total_profiled":1310},"omim":[{"mim_id":"615836","title":"SERINE/THREONINE PROTEIN KINASE 38-LIKE PROTEIN; STK38L","url":"https://www.omim.org/entry/615836"},{"mim_id":"611969","title":"MOB KINASE ACTIVATOR 2; MOB2","url":"https://www.omim.org/entry/611969"},{"mim_id":"606964","title":"SERINE/THREONINE PROTEIN KINASE 38; STK38","url":"https://www.omim.org/entry/606964"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MOB2"},"hgnc":{"alias_symbol":["HCCA2"],"prev_symbol":[]},"alphafold":{"accession":"Q70IA6","domains":[{"cath_id":"1.20.140.30","chopping":"23-209","consensus_level":"high","plddt":95.7224,"start":23,"end":209}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q70IA6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q70IA6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q70IA6-F1-predicted_aligned_error_v6.png","plddt_mean":85.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MOB2","jax_strain_url":"https://www.jax.org/strain/search?query=MOB2"},"sequence":{"accession":"Q70IA6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q70IA6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q70IA6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q70IA6"}},"corpus_meta":[{"pmid":"11747810","id":"PMC_11747810","title":"Yeast Cbk1 and Mob2 activate daughter-specific genetic programs to induce asymmetric cell fates.","date":"2001","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/11747810","citation_count":277,"is_preprint":false},{"pmid":"32286266","id":"PMC_32286266","title":"MOB2 suppresses GBM cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32286266","citation_count":63,"is_preprint":false},{"pmid":"20624913","id":"PMC_20624913","title":"Differential NDR/LATS interactions with the human MOB family reveal a negative role for human MOB2 in the regulation of human NDR kinases.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20624913","citation_count":52,"is_preprint":false},{"pmid":"21593210","id":"PMC_21593210","title":"CDK-dependent phosphorylation of Mob2 is essential for hyphal development in Candida albicans.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21593210","citation_count":38,"is_preprint":false},{"pmid":"14871942","id":"PMC_14871942","title":"The Ras/protein kinase A pathway acts in parallel with the Mob2/Cbk1 pathway to effect cell cycle progression and proper bud site selection.","date":"2004","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/14871942","citation_count":32,"is_preprint":false},{"pmid":"29593499","id":"PMC_29593499","title":"Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex.","date":"2018","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29593499","citation_count":28,"is_preprint":false},{"pmid":"21237165","id":"PMC_21237165","title":"The promotion of neurite formation in Neuro2A cells by mouse Mob2 protein.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21237165","citation_count":17,"is_preprint":false},{"pmid":"19834743","id":"PMC_19834743","title":"Function of Drosophila mob2 in photoreceptor morphogenesis.","date":"2009","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/19834743","citation_count":15,"is_preprint":false},{"pmid":"27387577","id":"PMC_27387577","title":"Crystal Structures, Stabilities, Electronic Properties, and Hardness of MoB2: First-Principles Calculations.","date":"2016","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27387577","citation_count":11,"is_preprint":false},{"pmid":"39863205","id":"PMC_39863205","title":"Astrocyte-conditional knockout of MOB2 inhibits the phenotypic conversion of reactive astrocytes from A1 to A2 following spinal cord injury in mice.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39863205","citation_count":9,"is_preprint":false},{"pmid":"23979583","id":"PMC_23979583","title":"Identification of Mob2, a novel regulator of larval neuromuscular junction morphology, in natural populations of Drosophila melanogaster.","date":"2013","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23979583","citation_count":9,"is_preprint":false},{"pmid":"28239681","id":"PMC_28239681","title":"The Possible Crosstalk of MOB2 With NDR1/2 Kinases in Cell Cycle and DNA Damage Signaling.","date":"2016","source":"Journal of cell signaling","url":"https://pubmed.ncbi.nlm.nih.gov/28239681","citation_count":6,"is_preprint":false},{"pmid":"34347361","id":"PMC_34347361","title":"The NDR kinase-MOB complex FgCot1-Mob2 regulates polarity and lipid metabolism in Fusarium graminearum.","date":"2021","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34347361","citation_count":4,"is_preprint":false},{"pmid":"23326134","id":"PMC_23326134","title":"Growth-inhibitory effects of MOB2 on human hepatic carcinoma cell line SMMC-7721.","date":"2012","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23326134","citation_count":1,"is_preprint":false},{"pmid":"40654237","id":"PMC_40654237","title":"Molybdenum Diboride (MoB2) Nanoparticles via a Facile Molten Salt Route: Synthesis, Characterization, Cytotoxicity, and Antibacterial Studies.","date":"2025","source":"ACS applied bio materials","url":"https://pubmed.ncbi.nlm.nih.gov/40654237","citation_count":0,"is_preprint":false},{"pmid":"41899447","id":"PMC_41899447","title":"MOB2 Loss Sensitizes Lung Cancer Cells to PARP Inhibition Through p53-Dependent DNA Damage Signaling.","date":"2026","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41899447","citation_count":0,"is_preprint":false},{"pmid":"11798894","id":"PMC_11798894","title":"[Cloning of liver cancer-related gene HCCA2 and association of that gene with liver cancer].","date":"2001","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/11798894","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8733,"output_tokens":2682,"usd":0.033215},"stage2":{"model":"claude-opus-4-6","input_tokens":6016,"output_tokens":2910,"usd":0.154245},"total_usd":0.18746,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Yeast Cbk1 kinase and its interacting protein Mob2 regulate asymmetric cell fates by activating and localizing the Ace2 transcription factor specifically to the daughter nucleus, thereby inducing daughter-specific gene expression programs including genes for cell wall degradation and cell separation.\",\n      \"method\": \"Genetic analysis, epistasis, localization studies, ectopic expression of Ace2\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, localization, ectopic expression), highly cited foundational study\",\n      \"pmids\": [\"11747810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The Mob2/Cbk1 pathway acts in parallel with the Ras/PKA pathway to control bud site selection and cell cycle progression in S. cerevisiae; Mob2 functions through proper localization of the Ace2 transcription factor, and the growth/budding defects of mob2Δ strains are suppressed by overexpression of the PKA catalytic subunit Tpk1.\",\n      \"method\": \"Genetic epistasis, double-mutant analysis, suppressor overexpression\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"14871942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human MOB2 (hMOB2) binds to the N-terminal region of NDR1 in a manner distinct from hMOB1A/B: it binds unphosphorylated NDR1, competes with hMOB1A for NDR binding, and acts as a negative regulator of NDR kinase activity. RNAi depletion of hMOB2 increases NDR kinase activity, and hMOB2 overexpression interferes with NDR-dependent death receptor signaling and centrosome overduplication.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, kinase activity assays, NDR binding competition assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays, RNAi, kinase assays, functional cellular readouts; multiple orthogonal methods\",\n      \"pmids\": [\"20624913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Candida albicans, the CDK Cdc28 phosphorylates Mob2 at four CDK consensus sites upon hyphal induction. Alanine mutations at these sites impair hyphal development, cause enlarged hyphal tips with illicit cell separation, and disrupt polarisome component maintenance at hyphal tips, defining a signaling pathway where Cdc28 controls Cbk1 NDR kinase through regulatory phosphorylation of Mob2.\",\n      \"method\": \"Site-directed mutagenesis of CDK phosphorylation sites, phenotypic analysis, localization assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phosphosite mutagenesis combined with functional and localization readouts\",\n      \"pmids\": [\"21593210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mouse Mob2 promotes neurite formation in Neuro2A cells; Mob2 knockdown decreases neurite outgrowth and alters actin cytoskeleton rearrangement, reducing phosphorylated Moesin levels, while Mob2 overexpression promotes neurite formation.\",\n      \"method\": \"RNAi knockdown, overexpression, actin cytoskeleton staining, phospho-Moesin western blot\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, loss- and gain-of-function with cellular readouts but limited mechanistic depth\",\n      \"pmids\": [\"21237165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Drosophila Mob2 (Dmob2) localizes to the apical membrane and later to the rhabdomere base of photoreceptor cells; RNAi knockdown of Dmob2 impairs rhabdomere formation and disrupts subcellular localization of phosphorylated Moesin and Crumbs in developing photoreceptors.\",\n      \"method\": \"Immunocytochemistry, RNAi knockdown, localization analysis\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization and RNAi with functional consequence, single lab\",\n      \"pmids\": [\"19834743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Mob2 regulates larval neuromuscular junction (NMJ) morphology by functioning as an NDR kinase activator; presynaptic expression of Mob2 is necessary and sufficient for NMJ growth regulation, and Mob2 interacts in a dominant, dose-dependent manner with the NDR kinase Tricornered (but not Warts) to control NMJ development.\",\n      \"method\": \"Genetic mapping, transformation rescue, dominant genetic interaction analysis, tissue-specific expression\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis, rescue experiments with specific NDR kinase interaction, single lab\",\n      \"pmids\": [\"23979583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MOB2 knockdown in the developing mouse cortex disrupts neuronal migration and positioning; reduced Mob2 expression increases phosphorylation of Filamin A (an actin cross-linking protein), and cilia positioning and number within migrating neurons is impaired. Reduction of an upstream modulator Dchs1 phenocopies this defect, placing MOB2 downstream of Dchs1 in a pathway controlling neuronal positioning.\",\n      \"method\": \"In utero knockdown, immunofluorescence, phospho-Filamin A western blot, genetic epistasis with Dchs1\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in vivo with defined molecular readout (Filamin A phosphorylation) and pathway placement\",\n      \"pmids\": [\"29593499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MOB2 acts as a tumor suppressor in GBM by negatively regulating the FAK/Akt pathway involving integrin signaling; MOB2 also interacts with and promotes PKA signaling in a cAMP-dependent manner, and MOB2 contributes to cAMP/PKA-mediated inactivation of FAK/Akt to suppress GBM cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, kinase pathway western blots, xenograft models, pharmacological manipulation (Forskolin, H89)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP for PKA interaction, multiple functional readouts, pharmacological validation, single lab\",\n      \"pmids\": [\"32286266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Astrocyte-conditional knockout of MOB2 inhibits the conversion of reactive astrocytes from A1 to A2 phenotype after spinal cord injury; mechanistically, MOB2 increases PI3K-AKT signaling activation to promote A1-to-A2 transformation, and the AKT activator sc79 rescues astrocyte subtype conversion and functional recovery in MOB2-CKO mice.\",\n      \"method\": \"Conditional knockout (GFAP-Cre), primary astrocyte reactive cell model, PI3K-AKT pathway analysis, pharmacological rescue with sc79\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined signaling pathway and pharmacological rescue, single lab\",\n      \"pmids\": [\"39863205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"hMOB2 depletion sensitizes p53-wild-type lung cancer cells (A549) to PARP inhibitors (olaparib, rucaparib) through enhanced p53 phosphorylation, persistent γH2AX accumulation, increased DNA strand breaks, and caspase-3-dependent apoptosis; this sensitization requires functional p53, as it is absent in p53-null cells and restored by p53 re-expression.\",\n      \"method\": \"siRNA knockdown, clonogenic assays, comet assays, immunofluorescence (γH2AX), caspase-3 activity, p53 reconstitution via retroviral transduction\",\n      \"journal\": \"Current issues in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, p53 dependency validated by reconstitution, single lab\",\n      \"pmids\": [\"41899447\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MOB2 is a regulatory cofactor that negatively modulates NDR kinases (NDR1/2) by competing with the activating MOB1 proteins for NDR N-terminal binding, keeping NDR in an unphosphorylated, less active state; in parallel, MOB2 participates in cAMP/PKA signaling, suppresses FAK/Akt pathway activity, promotes PI3K-AKT-dependent astrocyte phenotype switching, regulates neuronal migration via Filamin A phosphorylation, and in its founding yeast/fungal context, is phosphorylated by CDKs to enable NDR kinase (Cbk1)-dependent localization of the Ace2 transcription factor for asymmetric daughter-cell fate determination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MOB2 is a conserved regulatory scaffold that modulates NDR/LATS-family kinase signaling and multiple downstream pathways controlling cell polarity, morphogenesis, and neuronal positioning. In human cells, MOB2 binds the N-terminal region of NDR1/2 kinases in competition with the activating cofactor MOB1, thereby restraining NDR kinase activity and NDR-dependent processes including centrosome duplication and death receptor signaling [PMID:20624913]. Beyond NDR regulation, MOB2 participates in cAMP/PKA-mediated suppression of the FAK/Akt axis to limit glioblastoma cell migration [PMID:32286266], activates PI3K-AKT signaling to promote reactive astrocyte phenotype switching after spinal cord injury [PMID:39863205], and controls cortical neuronal migration through regulation of Filamin A phosphorylation downstream of the protocadherin Dchs1 [PMID:29593499]. In budding yeast and Candida, Mob2 partners with the NDR kinase Cbk1 to direct asymmetric daughter-cell gene expression via the Ace2 transcription factor, and CDK-dependent phosphorylation of Mob2 is essential for hyphal morphogenesis [PMID:11747810, PMID:21593210].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing MOB2 as an essential NDR kinase cofactor for asymmetric cell-fate determination resolved how daughter-specific transcription is achieved in yeast: Mob2 and Cbk1 cooperate to activate and localize the Ace2 transcription factor exclusively to the daughter nucleus.\",\n      \"evidence\": \"Genetic epistasis, localization, and ectopic Ace2 expression in S. cerevisiae\",\n      \"pmids\": [\"11747810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical mechanism by which Mob2 activates Cbk1 kinase was not resolved\",\n        \"Whether the Mob2-Cbk1 module has conserved functions in metazoans was unknown\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that the Mob2/Cbk1 pathway acts in parallel with Ras/PKA signaling for bud site selection expanded MOB2 function beyond Ace2 regulation and established cross-talk with cAMP/PKA signaling.\",\n      \"evidence\": \"Genetic suppression of mob2Δ by PKA catalytic subunit overexpression in S. cerevisiae\",\n      \"pmids\": [\"14871942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physical or biochemical basis of Mob2-PKA cross-talk was not defined\",\n        \"Whether this parallel relationship is conserved in mammalian cells was untested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Drosophila Mob2 localization studies in photoreceptors provided the first evidence that MOB2 functions at apical membranes to organize polarity determinants (Crumbs, phospho-Moesin) in a multicellular developmental context.\",\n      \"evidence\": \"Immunocytochemistry and RNAi knockdown in Drosophila photoreceptors\",\n      \"pmids\": [\"19834743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding partners mediating apical targeting were not identified\",\n        \"Whether MOB2 acts through an NDR kinase in this context was not tested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of human MOB2 as a negative regulator of NDR kinases — binding unphosphorylated NDR1 and competing with the activator MOB1 — inverted the expected activating role and established a competitive cofactor-switching mechanism for NDR regulation.\",\n      \"evidence\": \"Co-immunoprecipitation, competition binding assays, RNAi, kinase activity assays in human cells\",\n      \"pmids\": [\"20624913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for selective binding of MOB2 to unphosphorylated NDR was not determined\",\n        \"In vivo physiological contexts where MOB2-mediated NDR inhibition is critical were unclear\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"CDK-dependent phosphorylation of fungal Mob2 was shown to be required for hyphal morphogenesis, linking cell-cycle kinase signaling to Mob2-Cbk1 pathway output and polarisome maintenance at hyphal tips.\",\n      \"evidence\": \"CDK phosphosite mutagenesis, phenotypic and localization analysis in C. albicans\",\n      \"pmids\": [\"21593210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CDK phosphorylation alters Mob2-Cbk1 binding affinity or Mob2 localization directly was not biochemically resolved\",\n        \"Relevance of analogous phosphorylation events on mammalian MOB2 was unknown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mouse Mob2 was linked to neurite outgrowth and actin cytoskeleton remodeling via phospho-Moesin, providing the first mammalian neuronal function for MOB2.\",\n      \"evidence\": \"RNAi and overexpression in Neuro2A cells with phospho-Moesin readout\",\n      \"pmids\": [\"21237165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MOB2 acts through NDR kinases or an independent pathway in neurite formation was not determined\",\n        \"Moesin regulation was correlative; direct mechanism was not established\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Drosophila genetic analysis demonstrated that Mob2 acts specifically through the NDR kinase Tricornered (not Warts/LATS) to regulate presynaptic NMJ morphology, clarifying NDR-kinase specificity of MOB2 in a neuronal context.\",\n      \"evidence\": \"Genetic mapping, rescue, and dose-dependent dominant interactions at the Drosophila NMJ\",\n      \"pmids\": [\"23979583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MOB2 activates or inhibits Tricornered in this context was not biochemically resolved\",\n        \"Downstream substrates of Trc mediating NMJ growth were not identified\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"In vivo cortical knockdown revealed that MOB2 controls neuronal migration and cilia positioning by restraining Filamin A phosphorylation, placing MOB2 downstream of the protocadherin-family protein Dchs1 in a neuronal positioning pathway.\",\n      \"evidence\": \"In utero electroporation knockdown in mouse cortex, phospho-Filamin A analysis, epistasis with Dchs1\",\n      \"pmids\": [\"29593499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Kinase responsible for Filamin A hyperphosphorylation upon MOB2 loss was not identified\",\n        \"Whether this pathway involves NDR kinase modulation was not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"MOB2 was established as a tumor-suppressive factor in glioblastoma that physically interacts with PKA and promotes cAMP/PKA-dependent inactivation of the FAK/Akt axis, connecting MOB2 to integrin signaling and cancer cell invasion.\",\n      \"evidence\": \"Co-IP for PKA, overexpression/knockdown, pharmacological modulation (Forskolin, H89), xenograft models in GBM cells\",\n      \"pmids\": [\"32286266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding interface between MOB2 and PKA subunits was not mapped\",\n        \"Relationship between MOB2-PKA and MOB2-NDR functions was not clarified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conditional knockout demonstrated that astrocytic MOB2 activates PI3K-AKT signaling to promote A1-to-A2 reactive astrocyte conversion after spinal cord injury, with pharmacological AKT activation rescuing the phenotype.\",\n      \"evidence\": \"GFAP-Cre conditional knockout, primary astrocyte models, PI3K-AKT pathway analysis, sc79 rescue in vivo\",\n      \"pmids\": [\"39863205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which MOB2 activates PI3K-AKT is unknown — whether through NDR inhibition or an independent route\",\n        \"Whether MOB2 loss affects astrocyte-neuron signaling beyond phenotype switching was not explored\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"MOB2 depletion was found to sensitize p53-wild-type lung cancer cells to PARP inhibitors through enhanced p53 phosphorylation and persistent DNA damage, revealing a role for MOB2 in the DNA damage response that depends on functional p53.\",\n      \"evidence\": \"siRNA knockdown, clonogenic and comet assays, γH2AX immunofluorescence, caspase-3 activity, p53 reconstitution\",\n      \"pmids\": [\"41899447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking MOB2 to p53 phosphorylation and DNA repair proficiency is unknown\",\n        \"Whether MOB2's NDR-regulatory or PKA-regulatory functions mediate DNA damage sensitivity was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified mechanistic model integrating MOB2's NDR-inhibitory, PKA-stimulatory, and PI3K-AKT-activating functions remains unresolved; whether these represent independent activities or converge through a common scaffolding mechanism is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data exist for MOB2 in complex with any partner\",\n        \"Post-translational regulation of mammalian MOB2 (analogous to CDK phosphorylation in fungi) has not been characterized\",\n        \"Conditional knockout phenotypes in tissues beyond brain and spinal cord have not been reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NDR1\",\n      \"NDR2\",\n      \"CBK1\",\n      \"PRKACA\",\n      \"FLNA\",\n      \"DCHS1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}