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J Biol Chem. 2017 Aug 25;292(34):13947-13958. doi: 10.1074/jbc.M117.782896. Epub 2017 Jul 10.

Interplay between the phosphatase PHLPP1 and E3 ligase RNF41 stimulates proper kinetochore assembly via the outer-kinetochore protein SGT1.

Author information

1
From the Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India.
2
From the Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India msreddy@cdfd.org.in.

Abstract

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 multiprotein complex. However, the molecular mechanisms of kinetochore assembly have not yet been fully elucidated. In this study, we identified pleckstrin homology 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 ubiquitinated and degraded SGT1 in a phosphorylation-dependent manner. PHLPP1 dephosphorylated SGT1 at four conserved residues (Ser-17, Ser-249, Ser-289, and Thr-233) 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.

KEYWORDS:

E3 ubiquitin ligase; PHLPP1; RNF41; SGT1; cell cycle; kinetochore; mitosis; phosphatase

PMID:
28696259
PMCID:
PMC5572923
DOI:
10.1074/jbc.M117.782896
[Indexed for MEDLINE]
Free PMC Article

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