Interplay between the phosphatase PHLPP1 and an E3 ligase RNF41 stimulates proper kinetochore assembly via the outer-kinetochore protein SGT1 [Protein Synthesis and Degradation]

Kinetochores link chromosomes to spindle microtubules and are essential for accurate chromosome segregation during cell division. Kinetochores assemble at the centromeric region of chromosomes as a multi-protein complex. However, the molecular mechanisms of kinetochore assembly have not yet been fully elucidated. In this study, we identified PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) as a regulatory phosphatase that facilitates proper kinetochore assembly. We found that PHLPP1 interacted with the essential outer-kinetochore protein SGT1 and stabilized its protein levels. Loss of PHLPP1 from cells led to SGT1 degradation and thereby caused defective kinetochore assembly. We also found that the ring finger protein 41 (RNF41) as an E3 ligase that ubiquitinate and degrade SGT1 in a phosphorylation dependent manner. PHLPP1 dephosphorylated SGT1 at four conserved residues (S17, S249, S289, T233) and thereby prevented SGT1 from associating with RNF41, in turn, countering SGT1 degradation. Importantly, depletion of RNF41 or expression of a non-phosphorylatable SGT1 mutant rescued the kinetochore defects caused by the loss of PHLPP1. Taken together, our results suggest that PHLPP1 plays an important role in the assembly of kinetochores by counteracting RNF41-mediated SGT1 degradation.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2sYEPpx
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