{"gene":"MPHOSPH9","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":1996,"finding":"MPP9 (MPHOSPH9) is an M-phase phosphoprotein that becomes reactive with the MPM2 monoclonal antibody (which recognizes F-phosphoT-P-L-Q phosphorylation sites) specifically in M phase cells, indicating it is genuinely phosphorylated at M phase. In interphase, MPP9 localizes to the Golgi complex; in mitosis it redistributes throughout the cell.","method":"Expression cloning, immunoprecipitation with MPM2 antibody, immunofluorescence microscopy","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation with phospho-specific antibody and immunofluorescence in a single focused study; multiple orthogonal methods but single lab","pmids":["8885239"],"is_preprint":false},{"year":2018,"finding":"MPHOSPH9 (MPP9) is recruited by KIF24 to the distal end of the mother centriole, where it forms a ring-like structure and directly binds CEP97 to recruit the CP110-CEP97 complex. Loss of MPP9 causes abnormal primary cilia formation in growing cells and mouse kidneys. At the onset of ciliogenesis, MPP9 is phosphorylated by TTBK2 and then degraded via the ubiquitin-proteasome system, which facilitates removal of CP110 and CEP97 from the mother centriole distal end to permit ciliogenesis.","method":"Co-immunoprecipitation, pulldown assays, immunofluorescence, live-cell imaging, mouse kidney knockout phenotype analysis, ubiquitin-proteasome inhibitor experiments, kinase assay with TTBK2","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, direct binding assay, in vivo mouse model, kinase assay, proteasome inhibition) in a single rigorous study establishing mechanism","pmids":["30375385"],"is_preprint":false},{"year":2007,"finding":"MPHOSPH9 gene expression is synergistically upregulated in human SH-SY5Y neuroblastoma cells when both a glucocorticoid receptor agonist (dexamethasone) and a mu-opioid receptor agonist (DAMGO) are applied together, but not by either agent alone.","method":"Oligonucleotide microarray gene expression profiling validated by real-time RT-PCR","journal":"Cellular and molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression change confirmed by RT-PCR but no downstream mechanistic characterization of the protein itself; single lab, single cellular context","pmids":["17554624"],"is_preprint":false},{"year":2023,"finding":"CRISPR-Cas9 RNP deletion of a non-coding DNA element in primary human islet cells identified it as an in vivo enhancer of the MPHOSPH9 gene, establishing that MPHOSPH9 expression in pancreatic islet cells is regulated by a cis-regulatory enhancer element associated with a diabetes risk SNP.","method":"CRISPR-Cas9 ribonucleoprotein electroporation in primary human islet cells targeting a candidate enhancer element","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic perturbation of regulatory element with functional readout in primary human cells, single lab","pmids":["38205242"],"is_preprint":false}],"current_model":"MPHOSPH9 (MPP9) is an M-phase phosphoprotein that localizes to the Golgi complex in interphase and undergoes mitotic phosphorylation; its best-characterized function is at the mother centriole, where it is recruited by KIF24, forms a ring-like structure, and recruits the CP110-CEP97 complex via direct binding to CEP97 to suppress ciliogenesis — at ciliogenesis onset, TTBK2 phosphorylates MPP9 triggering its ubiquitin-proteasome-mediated degradation, which releases CP110-CEP97 and allows primary cilium formation."},"narrative":{"mechanistic_narrative":"MPHOSPH9 (MPP9) is a centriolar regulator of primary cilium formation that also behaves as an M-phase phosphoprotein, localizing to the Golgi complex during interphase and redistributing throughout the cell in mitosis when it becomes phosphorylated at MPM2-reactive sites [PMID:8885239]. Its best-characterized function is at the distal end of the mother centriole, where KIF24 recruits MPP9 to form a ring-like structure that directly binds CEP97 and thereby docks the CP110-CEP97 complex to suppress ciliogenesis [PMID:30375385]. At ciliogenesis onset, TTBK2 phosphorylates MPP9 to trigger its ubiquitin-proteasome-mediated degradation, releasing CP110-CEP97 from the centriole distal end and permitting cilium assembly; loss of MPP9 produces abnormal primary cilia in cultured cells and mouse kidney [PMID:30375385]. MPHOSPH9 expression is controlled in a tissue-specific manner by a cis-regulatory enhancer associated with a diabetes risk SNP in pancreatic islet cells [PMID:38205242].","teleology":[{"year":1996,"claim":"Established that MPHOSPH9 is a bona fide M-phase phosphoprotein with cell-cycle-dependent localization, raising the question of what process it serves at mitosis.","evidence":"Expression cloning with MPM2 phospho-specific antibody immunoprecipitation and immunofluorescence in M-phase versus interphase cells","pmids":["8885239"],"confidence":"Medium","gaps":["No molecular function or binding partner identified","Kinase responsible for M-phase phosphorylation not determined","Functional consequence of Golgi localization unknown"]},{"year":2018,"claim":"Defined MPP9's molecular function as a mother-centriole scaffold that gates ciliogenesis, resolving how CP110-CEP97 is recruited and removed at the centriole distal end.","evidence":"Co-IP, direct pulldown binding assays, immunofluorescence, live-cell imaging, TTBK2 kinase assay, proteasome inhibition, and mouse kidney knockout phenotyping","pmids":["30375385"],"confidence":"High","gaps":["E3 ligase mediating MPP9 ubiquitination not identified","Relationship between mitotic phosphorylation/Golgi pool and centriolar pool unresolved","Structural basis of the ring-like assembly and CEP97 interface not determined"]},{"year":2007,"claim":"Showed MPHOSPH9 transcription is responsive to combined glucocorticoid and mu-opioid receptor signaling, hinting at signal-dependent regulation, though without protein-level mechanism.","evidence":"Oligonucleotide microarray with RT-PCR validation in SH-SY5Y neuroblastoma cells co-treated with dexamethasone and DAMGO","pmids":["17554624"],"confidence":"Low","gaps":["No mechanistic characterization of the protein itself","Single cell context with no functional readout","Pathway connecting receptor signaling to MPHOSPH9 expression unknown"]},{"year":2023,"claim":"Identified a cis-regulatory enhancer controlling MPHOSPH9 expression in islet cells, linking the locus to diabetes genetics.","evidence":"CRISPR-Cas9 RNP deletion of a candidate enhancer in primary human islet cells with expression readout","pmids":["38205242"],"confidence":"Medium","gaps":["Mechanism linking islet MPHOSPH9 levels to diabetes phenotype not established","Whether centriolar/ciliary function underlies the islet effect unknown","Effect size and downstream targets not characterized"]},{"year":null,"claim":"How the mitotic/Golgi-associated phosphoprotein behavior relates to the centriolar ciliogenesis-gating function, and which E3 ligase executes TTBK2-triggered degradation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking M-phase phosphorylation to centriolar role","E3 ligase for MPP9 degradation unidentified","Structural detail of the centriolar ring and CEP97 binding interface lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1]}],"complexes":[],"partners":["KIF24","CEP97","CP110","TTBK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99550","full_name":"M-phase phosphoprotein 9","aliases":[],"length_aa":1183,"mass_kda":133.0,"function":"Negatively regulates cilia formation by recruiting the CP110-CEP97 complex (a negative regulator of ciliogenesis) at the distal end of the mother centriole in ciliary cells (PubMed:30375385). At the beginning of cilia formation, MPHOSPH9 undergoes TTBK2-mediated phosphorylation and degradation via the ubiquitin-proteasome system and removes itself and the CP110-CEP97 complex from the distal end of the mother centriole, which subsequently promotes cilia formation (PubMed:30375385)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Golgi apparatus membrane; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q99550/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MPHOSPH9","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MPHOSPH9","total_profiled":1310},"omim":[{"mim_id":"617833","title":"ZFHX2 ANTISENSE RNA 1, NONCODING; ZFHX2AS1","url":"https://www.omim.org/entry/617833"},{"mim_id":"605501","title":"M-PHASE PHOSPHOPROTEIN 9; MPHOSPH9","url":"https://www.omim.org/entry/605501"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":30.5}],"url":"https://www.proteinatlas.org/search/MPHOSPH9"},"hgnc":{"alias_symbol":["MPP9"],"prev_symbol":[]},"alphafold":{"accession":"Q99550","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99550","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99550-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99550-F1-predicted_aligned_error_v6.png","plddt_mean":54.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MPHOSPH9","jax_strain_url":"https://www.jax.org/strain/search?query=MPHOSPH9"},"sequence":{"accession":"Q99550","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99550.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99550/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99550"}},"corpus_meta":[{"pmid":"31420334","id":"PMC_31420334","title":"Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous 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becomes reactive with the MPM2 monoclonal antibody (which recognizes F-phosphoT-P-L-Q phosphorylation sites) specifically in M phase cells, indicating it is genuinely phosphorylated at M phase. In interphase, MPP9 localizes to the Golgi complex; in mitosis it redistributes throughout the cell.\",\n      \"method\": \"Expression cloning, immunoprecipitation with MPM2 antibody, immunofluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation with phospho-specific antibody and immunofluorescence in a single focused study; multiple orthogonal methods but single lab\",\n      \"pmids\": [\"8885239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MPHOSPH9 (MPP9) is recruited by KIF24 to the distal end of the mother centriole, where it forms a ring-like structure and directly binds CEP97 to recruit the CP110-CEP97 complex. Loss of MPP9 causes abnormal primary cilia formation in growing cells and mouse kidneys. At the onset of ciliogenesis, MPP9 is phosphorylated by TTBK2 and then degraded via the ubiquitin-proteasome system, which facilitates removal of CP110 and CEP97 from the mother centriole distal end to permit ciliogenesis.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, immunofluorescence, live-cell imaging, mouse kidney knockout phenotype analysis, ubiquitin-proteasome inhibitor experiments, kinase assay with TTBK2\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, direct binding assay, in vivo mouse model, kinase assay, proteasome inhibition) in a single rigorous study establishing mechanism\",\n      \"pmids\": [\"30375385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MPHOSPH9 gene expression is synergistically upregulated in human SH-SY5Y neuroblastoma cells when both a glucocorticoid receptor agonist (dexamethasone) and a mu-opioid receptor agonist (DAMGO) are applied together, but not by either agent alone.\",\n      \"method\": \"Oligonucleotide microarray gene expression profiling validated by real-time RT-PCR\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression change confirmed by RT-PCR but no downstream mechanistic characterization of the protein itself; single lab, single cellular context\",\n      \"pmids\": [\"17554624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR-Cas9 RNP deletion of a non-coding DNA element in primary human islet cells identified it as an in vivo enhancer of the MPHOSPH9 gene, establishing that MPHOSPH9 expression in pancreatic islet cells is regulated by a cis-regulatory enhancer element associated with a diabetes risk SNP.\",\n      \"method\": \"CRISPR-Cas9 ribonucleoprotein electroporation in primary human islet cells targeting a candidate enhancer element\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic perturbation of regulatory element with functional readout in primary human cells, single lab\",\n      \"pmids\": [\"38205242\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MPHOSPH9 (MPP9) is an M-phase phosphoprotein that localizes to the Golgi complex in interphase and undergoes mitotic phosphorylation; its best-characterized function is at the mother centriole, where it is recruited by KIF24, forms a ring-like structure, and recruits the CP110-CEP97 complex via direct binding to CEP97 to suppress ciliogenesis — at ciliogenesis onset, TTBK2 phosphorylates MPP9 triggering its ubiquitin-proteasome-mediated degradation, which releases CP110-CEP97 and allows primary cilium formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MPHOSPH9 (MPP9) is a centriolar regulator of primary cilium formation that also behaves as an M-phase phosphoprotein, localizing to the Golgi complex during interphase and redistributing throughout the cell in mitosis when it becomes phosphorylated at MPM2-reactive sites [#0]. Its best-characterized function is at the distal end of the mother centriole, where KIF24 recruits MPP9 to form a ring-like structure that directly binds CEP97 and thereby docks the CP110-CEP97 complex to suppress ciliogenesis [#1]. At ciliogenesis onset, TTBK2 phosphorylates MPP9 to trigger its ubiquitin-proteasome-mediated degradation, releasing CP110-CEP97 from the centriole distal end and permitting cilium assembly; loss of MPP9 produces abnormal primary cilia in cultured cells and mouse kidney [#1]. MPHOSPH9 expression is controlled in a tissue-specific manner by a cis-regulatory enhancer associated with a diabetes risk SNP in pancreatic islet cells [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that MPHOSPH9 is a bona fide M-phase phosphoprotein with cell-cycle-dependent localization, raising the question of what process it serves at mitosis.\",\n      \"evidence\": \"Expression cloning with MPM2 phospho-specific antibody immunoprecipitation and immunofluorescence in M-phase versus interphase cells\",\n      \"pmids\": [\"8885239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function or binding partner identified\", \"Kinase responsible for M-phase phosphorylation not determined\", \"Functional consequence of Golgi localization unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined MPP9's molecular function as a mother-centriole scaffold that gates ciliogenesis, resolving how CP110-CEP97 is recruited and removed at the centriole distal end.\",\n      \"evidence\": \"Co-IP, direct pulldown binding assays, immunofluorescence, live-cell imaging, TTBK2 kinase assay, proteasome inhibition, and mouse kidney knockout phenotyping\",\n      \"pmids\": [\"30375385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating MPP9 ubiquitination not identified\", \"Relationship between mitotic phosphorylation/Golgi pool and centriolar pool unresolved\", \"Structural basis of the ring-like assembly and CEP97 interface not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed MPHOSPH9 transcription is responsive to combined glucocorticoid and mu-opioid receptor signaling, hinting at signal-dependent regulation, though without protein-level mechanism.\",\n      \"evidence\": \"Oligonucleotide microarray with RT-PCR validation in SH-SY5Y neuroblastoma cells co-treated with dexamethasone and DAMGO\",\n      \"pmids\": [\"17554624\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic characterization of the protein itself\", \"Single cell context with no functional readout\", \"Pathway connecting receptor signaling to MPHOSPH9 expression unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a cis-regulatory enhancer controlling MPHOSPH9 expression in islet cells, linking the locus to diabetes genetics.\",\n      \"evidence\": \"CRISPR-Cas9 RNP deletion of a candidate enhancer in primary human islet cells with expression readout\",\n      \"pmids\": [\"38205242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking islet MPHOSPH9 levels to diabetes phenotype not established\", \"Whether centriolar/ciliary function underlies the islet effect unknown\", \"Effect size and downstream targets not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the mitotic/Golgi-associated phosphoprotein behavior relates to the centriolar ciliogenesis-gating function, and which E3 ligase executes TTBK2-triggered degradation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking M-phase phosphorylation to centriolar role\", \"E3 ligase for MPP9 degradation unidentified\", \"Structural detail of the centriolar ring and CEP97 binding interface lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KIF24\", \"CEP97\", \"CP110\", \"TTBK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}