{"gene":"MOB2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"In S. cerevisiae, Cbk1 kinase and its interacting protein Mob2 activate daughter-specific genetic programs by inducing activation and nuclear localization of the Ace2 transcription factor specifically to the daughter nucleus, thereby establishing asymmetric cell fates; ectopic localization of active Ace2 to mother nuclei was sufficient to activate daughter-specific genes in mothers.","method":"Genetic epistasis, localization experiments, transcriptional reporter assays in yeast","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, localization, reporter assays), foundational study replicated in follow-up work","pmids":["11747810"],"is_preprint":false},{"year":2004,"finding":"In S. cerevisiae, the Mob2/Cbk1 pathway acts in parallel with the Ras/PKA pathway to regulate proper bud site selection and cell cycle progression (G1/S); the growth and budding defects of mob2Δ ras2Δ double mutants are Ace2-independent but are suppressed by overexpression of PKA catalytic subunit Tpk1, placing Mob2/Cbk1 in a separate pathway from PKA.","method":"Genetic epistasis, double-mutant analysis, overexpression suppression in yeast","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis with multiple allele combinations, single lab","pmids":["14871942"],"is_preprint":false},{"year":2010,"finding":"Human MOB2 (hMOB2) binds to the N-terminal region of NDR1 kinase but in a manner distinct from hMOB1A/B: hMOB2 binds unphosphorylated NDR1, competes with hMOB1A for NDR binding, and acts as a negative regulator of NDR kinase activity. RNAi depletion of hMOB2 increased NDR kinase activity, while hMOB2 overexpression interfered with NDR functions in death receptor signaling and centrosome overduplication.","method":"Co-immunoprecipitation, RNAi knockdown with kinase activity assays, overexpression functional assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays, RNAi with kinase activity readout, and functional overexpression phenotypes; multiple orthogonal methods in one study","pmids":["20624913"],"is_preprint":false},{"year":2011,"finding":"In Candida albicans, the CDK Cdc28 phosphorylates Mob2 at four CDK consensus sites, and this phosphorylation is required for hyphal development. Mutation of all four sites to Ala impaired hyphal growth (short hyphae, enlarged tips, illicit cell separation) and disrupted maintenance of polarisome components at hyphal tips, defining a novel signaling axis in which Cdc28 controls the NDR kinase Cbk1 through regulatory phosphorylation of its activator Mob2.","method":"Site-directed mutagenesis of CDK phosphorylation sites, phosphorylation assays, localization studies in Candida albicans","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of phosphosites with clear morphogenetic phenotype and localization data; multiple orthogonal methods in single study","pmids":["21593210"],"is_preprint":false},{"year":2011,"finding":"Mouse Mob2 promotes neurite formation in Neuro2A cells; knockdown of Mob2 by RNAi decreased neurite formation in low-serum conditions and altered actin cytoskeleton rearrangement and reduced phosphorylated Moesin levels, while overexpression of Mob2 promoted neurite formation.","method":"RNAi knockdown, overexpression, morphological analysis, immunostaining for phospho-Moesin in Neuro2A cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype and biochemical readout, single lab, no direct mechanistic pathway placement","pmids":["21237165"],"is_preprint":false},{"year":2013,"finding":"Drosophila Mob2 regulates larval neuromuscular junction (NMJ) morphology; presynaptic expression of Mob2 is necessary and sufficient for NMJ growth control. Genetic interaction analysis showed that Mob2 interacts dominantly and dose-dependently with the NDR kinase Tricornered (but not with Warts) to regulate NMJ development, placing Mob2 specifically in the Tricornered NDR kinase pathway at the synapse.","method":"Genetic mapping, transformation rescue, dominant genetic interaction analysis, presynaptic-specific expression in Drosophila","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with kinase specificity testing, rescue experiments; single lab","pmids":["23979583"],"is_preprint":false},{"year":2018,"finding":"MOB2 is required for correct neuronal positioning in the developing mouse cortex; Mob2 knockdown impaired neuronal migration, disrupted cilia positioning and number in migrating neurons, and increased phosphorylation of Filamin A, an actin cross-linking protein. Loss-of-function variants in MOB2 were identified in a patient with periventricular nodular heterotopia.","method":"In utero electroporation knockdown in developing mouse cortex, immunostaining, protein turnover assays, patient variant functional characterization","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with defined cellular phenotypes and biochemical readout (Filamin A phosphorylation), single lab","pmids":["29593499"],"is_preprint":false},{"year":2020,"finding":"In GBM cells, MOB2 negatively regulates the FAK/Akt pathway involving integrin signaling, and interacts with and promotes PKA signaling in a cAMP-dependent manner. MOB2 contributes to cAMP/PKA-mediated inactivation of FAK/Akt, thereby suppressing GBM cell migration and invasion. The cAMP activator Forskolin increased MOB2 expression while PKA inhibitor H89 decreased it.","method":"Co-immunoprecipitation, RNAi knockdown, overexpression, pharmacological modulation (Forskolin, H89), xenograft and chick CAM models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for interaction, loss/gain-of-function with pathway readouts, multiple models; single lab","pmids":["32286266"],"is_preprint":false},{"year":2025,"finding":"Conditional knockout of MOB2 in astrocytes (MOB2GFAP-CKO mice) inhibits the phenotypic conversion of reactive astrocytes from A1 (proinflammatory) to A2 (anti-inflammatory) after spinal cord injury; mechanistically, MOB2 increases PI3K-AKT signaling activation to promote A1-to-A2 transformation, and AKT activator sc79 reversed the subtype transformation defect in MOB2-deficient mice.","method":"Conditional knockout mice, primary astrocyte reactive cell model, pharmacological rescue with AKT activator, spinal cord injury model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotype, pharmacological epistasis via AKT activator rescue; single lab","pmids":["39863205"],"is_preprint":false},{"year":2026,"finding":"hMOB2 depletion sensitizes A549 lung cancer cells to PARP inhibitors (olaparib, rucaparib) in a p53-dependent manner; hMOB2 loss enhanced p53 phosphorylation, persistent γH2AX accumulation, increased DNA strand breaks, and caspase-3-dependent apoptosis upon PARP inhibitor treatment. Sensitization was absent in p53-null H1299 cells but restored upon p53 re-expression, indicating hMOB2 regulates PARP inhibitor sensitivity through p53-dependent DNA damage signaling.","method":"siRNA knockdown, clonogenic and viability assays, Western blotting, immunofluorescence, comet assays, caspase-3 activity assays, p53 reconstitution via retroviral transduction","journal":"Current issues in molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods, p53 epistasis confirmed by re-expression rescue; single lab","pmids":["41899447"],"is_preprint":false},{"year":2009,"finding":"Drosophila Mob2 (Dmob2) localizes to the apical membrane of developing photoreceptor cells and is gradually confined to the rhabdomere base as development proceeds. RNAi knockdown of Dmob2 impairs rhabdomere formation and disrupts subcellular localization of phosphorylated Moesin and Crumbs in developing photoreceptors.","method":"Immunocytochemistry with custom antibody, RNAi knockdown during eye development, localization assays in Drosophila","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization tied to functional consequence (rhabdomere formation), RNAi knockdown with multiple markers; single lab","pmids":["19834743"],"is_preprint":false}],"current_model":"MOB2 is a conserved NDR kinase-associated protein that acts as a negative regulator of human NDR1/2 kinases by competing with the activating MOB1A/B proteins for binding to unphosphorylated NDR kinase; in parallel, MOB2 regulates asymmetric cell fate (via Cbk1/Ace2 in yeast), neuronal migration (via Filamin A phosphorylation and cilia positioning), GBM cell migration and invasion (via FAK/Akt and cAMP/PKA signaling), astrocyte phenotypic switching (via PI3K-AKT), and PARP inhibitor sensitivity (via p53-dependent DNA damage signaling), with its activity further controlled by CDK-dependent phosphorylation of Mob2 itself."},"narrative":{"mechanistic_narrative":"MOB2 is a conserved NDR (nuclear Dbf2-related) kinase-associated protein that couples NDR-family kinase signaling to cell polarity, cytoskeletal organization, and cell-fate decisions across fungi, invertebrates, and mammals [PMID:11747810, PMID:20624913, PMID:23979583]. In human cells, hMOB2 binds the N-terminal region of NDR1 in an unphosphorylated state and competes with the activating cofactors hMOB1A/B, thereby acting as a negative regulator of NDR kinase activity in death-receptor signaling and centrosome duplication [PMID:20624913]. The activity of Mob2 itself is gated by CDK-dependent phosphorylation, establishing a regulatory layer above the NDR kinase it activates [PMID:21593210]. In yeast, the Cbk1–Mob2 module drives asymmetric daughter-cell fate by directing nuclear accumulation of the Ace2 transcription factor [PMID:11747810], and operates in parallel to Ras/PKA signaling [PMID:14871942]. In metazoan neurons, Mob2 controls cytoskeletal remodeling and cilia positioning: it promotes neurite outgrowth with altered phospho-Moesin levels [PMID:21237165], regulates Tricornered-dependent neuromuscular junction growth [PMID:23979583], and is required for cortical neuronal migration through control of cilia positioning and Filamin A phosphorylation, with loss-of-function MOB2 variants identified in periventricular nodular heterotopia [PMID:29593499]. In disease and injury contexts MOB2 modulates cell migration and phenotypic state by acting on FAK/Akt and cAMP/PKA signaling in glioblastoma [PMID:32286266] and PI3K–AKT signaling in reactive astrocytes [PMID:39863205], and its depletion sensitizes lung cancer cells to PARP inhibitors via p53-dependent DNA damage signaling [PMID:41899447].","teleology":[{"year":2001,"claim":"Established the founding mechanistic role of the Mob2 module: how a cell generates asymmetric daughter-specific gene expression, by showing Cbk1–Mob2 directs Ace2 transcription factor activation and nuclear localization specifically to the daughter nucleus.","evidence":"Genetic epistasis, localization, and transcriptional reporter assays in S. cerevisiae","pmids":["11747810"],"confidence":"High","gaps":["Does not define the biochemical basis of Mob2–Cbk1 activation of Ace2","No structural detail of the Mob2–kinase interaction"]},{"year":2004,"claim":"Resolved whether Mob2/Cbk1 acts within or alongside Ras/PKA in cell cycle and bud-site control, showing it functions as a separate, Ace2-independent pathway.","evidence":"Double-mutant epistasis and overexpression suppression in yeast","pmids":["14871942"],"confidence":"Medium","gaps":["Molecular targets of the Ace2-independent Mob2/Cbk1 function not identified","Single-organism genetic inference only"]},{"year":2009,"claim":"Addressed where Mob2 acts in polarized cells, linking its apical/rhabdomere localization to membrane and cytoskeletal protein positioning during photoreceptor morphogenesis.","evidence":"Immunocytochemistry and RNAi knockdown in Drosophila eye development","pmids":["19834743"],"confidence":"Medium","gaps":["Direct kinase partner at the rhabdomere not established","Mechanism linking Mob2 to Moesin/Crumbs localization unknown"]},{"year":2010,"claim":"Defined the core biochemical role of human MOB2, showing it binds unphosphorylated NDR1, competes with the activator hMOB1A, and thereby negatively regulates NDR kinase activity — distinguishing it from the activating MOB1 cofactors.","evidence":"Co-immunoprecipitation, RNAi with kinase activity assays, and overexpression functional assays in human cells","pmids":["20624913"],"confidence":"High","gaps":["Structural basis of competitive binding not resolved","Whether MOB2 has any positive NDR-independent functions not addressed"]},{"year":2011,"claim":"Identified an upstream control layer on the Mob2 module, showing CDK (Cdc28) phosphorylates Mob2 at four consensus sites to drive hyphal morphogenesis and polarisome maintenance.","evidence":"Phosphosite mutagenesis, phosphorylation assays, and localization in Candida albicans","pmids":["21593210"],"confidence":"High","gaps":["Whether mammalian MOB2 is similarly CDK-regulated not tested","Downstream effectors of phosphorylated Mob2 not fully mapped"]},{"year":2011,"claim":"Extended Mob2 function to metazoan neuronal cytoskeletal remodeling, showing it promotes neurite formation with concomitant changes in actin organization and phospho-Moesin.","evidence":"RNAi knockdown, overexpression, and phospho-Moesin immunostaining in Neuro2A cells","pmids":["21237165"],"confidence":"Medium","gaps":["No direct kinase pathway placement","Relationship to NDR regulatory activity not tested"]},{"year":2013,"claim":"Pinpointed kinase specificity for Mob2 at the synapse, showing it acts dose-dependently with Tricornered (not Warts) NDR kinase to control neuromuscular junction growth.","evidence":"Genetic interaction, rescue, and presynaptic-specific expression in Drosophila","pmids":["23979583"],"confidence":"Medium","gaps":["Biochemical mode of Mob2–Tricornered interaction not defined","Downstream synaptic effectors unidentified"]},{"year":2018,"claim":"Linked MOB2 to mammalian brain development and human disease, showing it is required for cortical neuronal migration via cilia positioning and Filamin A phosphorylation, with loss-of-function variants in periventricular nodular heterotopia.","evidence":"In utero electroporation knockdown, immunostaining, turnover assays, and patient variant characterization in mouse","pmids":["29593499"],"confidence":"Medium","gaps":["Direct kinase mediating Filamin A phosphorylation not established","Genotype-phenotype link based on limited patient data"]},{"year":2020,"claim":"Defined a cancer-context signaling role, showing MOB2 promotes cAMP/PKA signaling and negatively regulates FAK/Akt to suppress glioblastoma migration and invasion.","evidence":"Co-IP, knockdown/overexpression, pharmacological modulation, and xenograft/CAM models","pmids":["32286266"],"confidence":"Medium","gaps":["Direct PKA-MOB2 binding interface not mapped","Connection between this role and NDR kinase regulation unclear"]},{"year":2025,"claim":"Showed MOB2 governs reactive astrocyte phenotypic switching after injury by driving PI3K-AKT activation to promote the A1-to-A2 conversion.","evidence":"Conditional knockout mice, primary astrocyte model, and AKT-activator rescue in a spinal cord injury model","pmids":["39863205"],"confidence":"Medium","gaps":["Mechanism by which MOB2 activates PI3K-AKT not defined","Whether NDR kinases participate in astrocyte switching untested"]},{"year":2026,"claim":"Connected MOB2 to DNA damage and therapeutic vulnerability, showing its depletion sensitizes lung cancer cells to PARP inhibitors through p53-dependent damage signaling and apoptosis.","evidence":"siRNA knockdown, clonogenic/comet/caspase assays, and p53 reconstitution in lung cancer cells","pmids":["41899447"],"confidence":"Medium","gaps":["Mechanism linking MOB2 to p53 signaling not defined","Whether effect requires NDR kinase activity unknown"]},{"year":null,"claim":"How MOB2's biochemical role as a negative NDR kinase regulator mechanistically connects to its diverse in vivo functions in cilia positioning, cytoskeletal remodeling, PKA/AKT signaling, and p53-dependent DNA damage responses remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical pathway linking NDR regulation to the cilia/cytoskeletal and PKA/AKT/p53 phenotypes","No structural model of human MOB2 complexes","Direct substrates downstream of MOB2-regulated kinases not catalogued in mammals"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,5]}],"complexes":[],"partners":["NDR1","MOB1A","CBK1","TRICORNERED","FAK","AKT","PKA","FILAMIN A"],"other_free_text":[]}},"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":53,"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":29,"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":10,"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":"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":"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9119,"output_tokens":2978,"usd":0.036013,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10348,"output_tokens":3630,"usd":0.071245,"stage2_stop_reason":"end_turn"},"total_usd":0.107258,"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\": 2001,\n      \"finding\": \"In S. cerevisiae, Cbk1 kinase and its interacting protein Mob2 activate daughter-specific genetic programs by inducing activation and nuclear localization of the Ace2 transcription factor specifically to the daughter nucleus, thereby establishing asymmetric cell fates; ectopic localization of active Ace2 to mother nuclei was sufficient to activate daughter-specific genes in mothers.\",\n      \"method\": \"Genetic epistasis, localization experiments, transcriptional reporter assays in yeast\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, localization, reporter assays), foundational study replicated in follow-up work\",\n      \"pmids\": [\"11747810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In S. cerevisiae, the Mob2/Cbk1 pathway acts in parallel with the Ras/PKA pathway to regulate proper bud site selection and cell cycle progression (G1/S); the growth and budding defects of mob2Δ ras2Δ double mutants are Ace2-independent but are suppressed by overexpression of PKA catalytic subunit Tpk1, placing Mob2/Cbk1 in a separate pathway from PKA.\",\n      \"method\": \"Genetic epistasis, double-mutant analysis, overexpression suppression in yeast\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis with multiple allele combinations, 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 kinase but in a manner distinct from hMOB1A/B: hMOB2 binds unphosphorylated NDR1, competes with hMOB1A for NDR binding, and acts as a negative regulator of NDR kinase activity. RNAi depletion of hMOB2 increased NDR kinase activity, while hMOB2 overexpression interfered with NDR functions in death receptor signaling and centrosome overduplication.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown with kinase activity assays, overexpression functional assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays, RNAi with kinase activity readout, and functional overexpression phenotypes; multiple orthogonal methods in one study\",\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, and this phosphorylation is required for hyphal development. Mutation of all four sites to Ala impaired hyphal growth (short hyphae, enlarged tips, illicit cell separation) and disrupted maintenance of polarisome components at hyphal tips, defining a novel signaling axis in which Cdc28 controls the NDR kinase Cbk1 through regulatory phosphorylation of its activator Mob2.\",\n      \"method\": \"Site-directed mutagenesis of CDK phosphorylation sites, phosphorylation assays, localization studies in Candida albicans\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of phosphosites with clear morphogenetic phenotype and localization data; multiple orthogonal methods in single study\",\n      \"pmids\": [\"21593210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mouse Mob2 promotes neurite formation in Neuro2A cells; knockdown of Mob2 by RNAi decreased neurite formation in low-serum conditions and altered actin cytoskeleton rearrangement and reduced phosphorylated Moesin levels, while overexpression of Mob2 promoted neurite formation.\",\n      \"method\": \"RNAi knockdown, overexpression, morphological analysis, immunostaining for phospho-Moesin in Neuro2A cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype and biochemical readout, single lab, no direct mechanistic pathway placement\",\n      \"pmids\": [\"21237165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Mob2 regulates larval neuromuscular junction (NMJ) morphology; presynaptic expression of Mob2 is necessary and sufficient for NMJ growth control. Genetic interaction analysis showed that Mob2 interacts dominantly and dose-dependently with the NDR kinase Tricornered (but not with Warts) to regulate NMJ development, placing Mob2 specifically in the Tricornered NDR kinase pathway at the synapse.\",\n      \"method\": \"Genetic mapping, transformation rescue, dominant genetic interaction analysis, presynaptic-specific expression in Drosophila\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with kinase specificity testing, rescue experiments; single lab\",\n      \"pmids\": [\"23979583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MOB2 is required for correct neuronal positioning in the developing mouse cortex; Mob2 knockdown impaired neuronal migration, disrupted cilia positioning and number in migrating neurons, and increased phosphorylation of Filamin A, an actin cross-linking protein. Loss-of-function variants in MOB2 were identified in a patient with periventricular nodular heterotopia.\",\n      \"method\": \"In utero electroporation knockdown in developing mouse cortex, immunostaining, protein turnover assays, patient variant functional characterization\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with defined cellular phenotypes and biochemical readout (Filamin A phosphorylation), single lab\",\n      \"pmids\": [\"29593499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In GBM cells, MOB2 negatively regulates the FAK/Akt pathway involving integrin signaling, and interacts with and promotes PKA signaling in a cAMP-dependent manner. MOB2 contributes to cAMP/PKA-mediated inactivation of FAK/Akt, thereby suppressing GBM cell migration and invasion. The cAMP activator Forskolin increased MOB2 expression while PKA inhibitor H89 decreased it.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, overexpression, pharmacological modulation (Forskolin, H89), xenograft and chick CAM models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for interaction, loss/gain-of-function with pathway readouts, multiple models; single lab\",\n      \"pmids\": [\"32286266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of MOB2 in astrocytes (MOB2GFAP-CKO mice) inhibits the phenotypic conversion of reactive astrocytes from A1 (proinflammatory) to A2 (anti-inflammatory) after spinal cord injury; mechanistically, MOB2 increases PI3K-AKT signaling activation to promote A1-to-A2 transformation, and AKT activator sc79 reversed the subtype transformation defect in MOB2-deficient mice.\",\n      \"method\": \"Conditional knockout mice, primary astrocyte reactive cell model, pharmacological rescue with AKT activator, spinal cord injury model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotype, pharmacological epistasis via AKT activator rescue; single lab\",\n      \"pmids\": [\"39863205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"hMOB2 depletion sensitizes A549 lung cancer cells to PARP inhibitors (olaparib, rucaparib) in a p53-dependent manner; hMOB2 loss enhanced p53 phosphorylation, persistent γH2AX accumulation, increased DNA strand breaks, and caspase-3-dependent apoptosis upon PARP inhibitor treatment. Sensitization was absent in p53-null H1299 cells but restored upon p53 re-expression, indicating hMOB2 regulates PARP inhibitor sensitivity through p53-dependent DNA damage signaling.\",\n      \"method\": \"siRNA knockdown, clonogenic and viability assays, Western blotting, immunofluorescence, comet assays, caspase-3 activity assays, p53 reconstitution via retroviral transduction\",\n      \"journal\": \"Current issues in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods, p53 epistasis confirmed by re-expression rescue; single lab\",\n      \"pmids\": [\"41899447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Drosophila Mob2 (Dmob2) localizes to the apical membrane of developing photoreceptor cells and is gradually confined to the rhabdomere base as development proceeds. RNAi knockdown of Dmob2 impairs rhabdomere formation and disrupts subcellular localization of phosphorylated Moesin and Crumbs in developing photoreceptors.\",\n      \"method\": \"Immunocytochemistry with custom antibody, RNAi knockdown during eye development, localization assays in Drosophila\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization tied to functional consequence (rhabdomere formation), RNAi knockdown with multiple markers; single lab\",\n      \"pmids\": [\"19834743\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MOB2 is a conserved NDR kinase-associated protein that acts as a negative regulator of human NDR1/2 kinases by competing with the activating MOB1A/B proteins for binding to unphosphorylated NDR kinase; in parallel, MOB2 regulates asymmetric cell fate (via Cbk1/Ace2 in yeast), neuronal migration (via Filamin A phosphorylation and cilia positioning), GBM cell migration and invasion (via FAK/Akt and cAMP/PKA signaling), astrocyte phenotypic switching (via PI3K-AKT), and PARP inhibitor sensitivity (via p53-dependent DNA damage signaling), with its activity further controlled by CDK-dependent phosphorylation of Mob2 itself.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MOB2 is a conserved NDR (nuclear Dbf2-related) kinase-associated protein that couples NDR-family kinase signaling to cell polarity, cytoskeletal organization, and cell-fate decisions across fungi, invertebrates, and mammals [#0, #2, #5]. In human cells, hMOB2 binds the N-terminal region of NDR1 in an unphosphorylated state and competes with the activating cofactors hMOB1A/B, thereby acting as a negative regulator of NDR kinase activity in death-receptor signaling and centrosome duplication [#2]. The activity of Mob2 itself is gated by CDK-dependent phosphorylation, establishing a regulatory layer above the NDR kinase it activates [#3]. In yeast, the Cbk1–Mob2 module drives asymmetric daughter-cell fate by directing nuclear accumulation of the Ace2 transcription factor [#0], and operates in parallel to Ras/PKA signaling [#1]. In metazoan neurons, Mob2 controls cytoskeletal remodeling and cilia positioning: it promotes neurite outgrowth with altered phospho-Moesin levels [#4], regulates Tricornered-dependent neuromuscular junction growth [#5], and is required for cortical neuronal migration through control of cilia positioning and Filamin A phosphorylation, with loss-of-function MOB2 variants identified in periventricular nodular heterotopia [#6]. In disease and injury contexts MOB2 modulates cell migration and phenotypic state by acting on FAK/Akt and cAMP/PKA signaling in glioblastoma [#7] and PI3K–AKT signaling in reactive astrocytes [#8], and its depletion sensitizes lung cancer cells to PARP inhibitors via p53-dependent DNA damage signaling [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the founding mechanistic role of the Mob2 module: how a cell generates asymmetric daughter-specific gene expression, by showing Cbk1–Mob2 directs Ace2 transcription factor activation and nuclear localization specifically to the daughter nucleus.\",\n      \"evidence\": \"Genetic epistasis, localization, and transcriptional reporter assays in S. cerevisiae\",\n      \"pmids\": [\"11747810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the biochemical basis of Mob2–Cbk1 activation of Ace2\", \"No structural detail of the Mob2–kinase interaction\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved whether Mob2/Cbk1 acts within or alongside Ras/PKA in cell cycle and bud-site control, showing it functions as a separate, Ace2-independent pathway.\",\n      \"evidence\": \"Double-mutant epistasis and overexpression suppression in yeast\",\n      \"pmids\": [\"14871942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets of the Ace2-independent Mob2/Cbk1 function not identified\", \"Single-organism genetic inference only\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Addressed where Mob2 acts in polarized cells, linking its apical/rhabdomere localization to membrane and cytoskeletal protein positioning during photoreceptor morphogenesis.\",\n      \"evidence\": \"Immunocytochemistry and RNAi knockdown in Drosophila eye development\",\n      \"pmids\": [\"19834743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase partner at the rhabdomere not established\", \"Mechanism linking Mob2 to Moesin/Crumbs localization unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the core biochemical role of human MOB2, showing it binds unphosphorylated NDR1, competes with the activator hMOB1A, and thereby negatively regulates NDR kinase activity — distinguishing it from the activating MOB1 cofactors.\",\n      \"evidence\": \"Co-immunoprecipitation, RNAi with kinase activity assays, and overexpression functional assays in human cells\",\n      \"pmids\": [\"20624913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of competitive binding not resolved\", \"Whether MOB2 has any positive NDR-independent functions not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified an upstream control layer on the Mob2 module, showing CDK (Cdc28) phosphorylates Mob2 at four consensus sites to drive hyphal morphogenesis and polarisome maintenance.\",\n      \"evidence\": \"Phosphosite mutagenesis, phosphorylation assays, and localization in Candida albicans\",\n      \"pmids\": [\"21593210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian MOB2 is similarly CDK-regulated not tested\", \"Downstream effectors of phosphorylated Mob2 not fully mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended Mob2 function to metazoan neuronal cytoskeletal remodeling, showing it promotes neurite formation with concomitant changes in actin organization and phospho-Moesin.\",\n      \"evidence\": \"RNAi knockdown, overexpression, and phospho-Moesin immunostaining in Neuro2A cells\",\n      \"pmids\": [\"21237165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct kinase pathway placement\", \"Relationship to NDR regulatory activity not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Pinpointed kinase specificity for Mob2 at the synapse, showing it acts dose-dependently with Tricornered (not Warts) NDR kinase to control neuromuscular junction growth.\",\n      \"evidence\": \"Genetic interaction, rescue, and presynaptic-specific expression in Drosophila\",\n      \"pmids\": [\"23979583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical mode of Mob2–Tricornered interaction not defined\", \"Downstream synaptic effectors unidentified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked MOB2 to mammalian brain development and human disease, showing it is required for cortical neuronal migration via cilia positioning and Filamin A phosphorylation, with loss-of-function variants in periventricular nodular heterotopia.\",\n      \"evidence\": \"In utero electroporation knockdown, immunostaining, turnover assays, and patient variant characterization in mouse\",\n      \"pmids\": [\"29593499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase mediating Filamin A phosphorylation not established\", \"Genotype-phenotype link based on limited patient data\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a cancer-context signaling role, showing MOB2 promotes cAMP/PKA signaling and negatively regulates FAK/Akt to suppress glioblastoma migration and invasion.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, pharmacological modulation, and xenograft/CAM models\",\n      \"pmids\": [\"32286266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PKA-MOB2 binding interface not mapped\", \"Connection between this role and NDR kinase regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed MOB2 governs reactive astrocyte phenotypic switching after injury by driving PI3K-AKT activation to promote the A1-to-A2 conversion.\",\n      \"evidence\": \"Conditional knockout mice, primary astrocyte model, and AKT-activator rescue in a spinal cord injury model\",\n      \"pmids\": [\"39863205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MOB2 activates PI3K-AKT not defined\", \"Whether NDR kinases participate in astrocyte switching untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected MOB2 to DNA damage and therapeutic vulnerability, showing its depletion sensitizes lung cancer cells to PARP inhibitors through p53-dependent damage signaling and apoptosis.\",\n      \"evidence\": \"siRNA knockdown, clonogenic/comet/caspase assays, and p53 reconstitution in lung cancer cells\",\n      \"pmids\": [\"41899447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking MOB2 to p53 signaling not defined\", \"Whether effect requires NDR kinase activity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MOB2's biochemical role as a negative NDR kinase regulator mechanistically connects to its diverse in vivo functions in cilia positioning, cytoskeletal remodeling, PKA/AKT signaling, and p53-dependent DNA damage responses remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying biochemical pathway linking NDR regulation to the cilia/cytoskeletal and PKA/AKT/p53 phenotypes\", \"No structural model of human MOB2 complexes\", \"Direct substrates downstream of MOB2-regulated kinases not catalogued in mammals\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NDR1\", \"MOB1A\", \"Cbk1\", \"Tricornered\", \"FAK\", \"Akt\", \"PKA\", \"Filamin A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}