MPHOSPH9

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).

1. 1996 Medium

   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

   PMID:8885239

   Open questions at the time

   • No molecular function or binding partner identified
   • Kinase responsible for M-phase phosphorylation not determined
   • Functional consequence of Golgi localization unknown
2. 2018 High

   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

   PMID:30375385

   Open questions at the time

   • 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
3. 2007 Low

   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

   PMID:17554624

   Open questions at the time

   • No mechanistic characterization of the protein itself
   • Single cell context with no functional readout
   • Pathway connecting receptor signaling to MPHOSPH9 expression unknown
4. 2023 Medium

   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

   PMID:38205242

   Open questions at the time

   • 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

• How the mitotic/Golgi-associated phosphoprotein behavior relates to the centriolar ciliogenesis-gating function, and which E3 ligase executes TTBK2-triggered degradation, remain unresolved.
• 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