PMID: 33806062 eFIP 1 Check other iTextMine results Issue Report
Title
| 1. | Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression. |
Abstract
| 2. | The timing of centrosome separation and the distance moved apart influence the formation of the bipolar spindle, affecting chromosome stability. |
| 3. | Epidermal growth factor receptor (EGFR) signaling induces early centrosome separation through downstream G protein-coupled receptor kinase GRK2, which phosphorylates the Hippo pathway component MST2 (Mammalian STE20-like protein kinase 2), in turn allowing NIMA kinase Nek2A activation for centrosomal linker disassembly. |
| 4. | However, the mechanisms that counterbalance centrosome disjunction and separation remain poorly understood. |
| 5. | We unveil that timely degradation of GRK2 by the E3 ligase Mdm2 limits centrosome separation in the G2. |
| 6. | Both knockout expression and catalytic inhibition of Mdm2 result in GRK2 accumulation and enhanced centrosome separation before mitosis onset. |
| 7. | Phosphorylation of GRK2 on residue S670 enables a complex pattern of non-K48-linked polyubiquitin chains assembled by Mdm2, which correlate with kinase protein degradation. |
| 8. | Remarkably, GRK2-S670A protein fails to phosphorylate MST2 despite overcoming Mdm2-dependent degradation, which results in defective centrosome separation, shorter spindles, and abnormal chromosome congression. |
| 9. | Conversely, extra levels of wild-type kinase in the G2 cause increased inter-centrosome distances with longer spindles, also converging in congression issues. |
| 10. | Our findings show that the signals enabling activity of the GRK2/MST2/Nek2A axis for separation also switches on Mdm2 degradation of GRK2 to ensure accurate centrosome dynamics and proper mitotic spindle functionality. |
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Legend: SUBSTRATE KINASE INTERACTANT SITE GENE MIRNA ANOMALY EXPRESSION DISEASE OUTCOME/RESPONSE SR_DRUG DRUG CELL TRIGGER Normalized
Tool: eFIP
| PTM enzyme | Substrate | Site | Impact | Interactant | Sentence |
|---|---|---|---|---|---|
| GRK2 (P25098) | Ser-670 | enables | non-K48-linked polyubiquitin chains | 7 |