TOPK and PTEN participate in CHFR mediated mitotic checkpoint

Swapnil R Shinde,Narmadha Reddy Gangula,Sridhar Kavela,Vimal Pandey,Subbareddy Maddika

doi:10.1016/j.cellsig.2013.08.013

Abstract

Mitotic progression is regulated by co-ordinated action of several proteins and is crucial for the maintenance of genomic stability. CHFR (Check point protein with FHA and RING domains) is an E3 ubiquitin ligase and a checkpoint protein that regulates entry into mitosis. But the molecular players involved in CHFR mediated mitotic checkpoint are not completely understood. In this study, we identified TOPK/PBK, a serine/threonine kinase and PTEN, a lipid phosphatase to play an important role in CHFR mediated mitotic transitions. We demonstrated that CHFR ubiquitinates and regulates TOPK levels, which is essential for its checkpoint function. Moreover, TOPK phosphorylates and inactivates PTEN, which in turn activates Akt that leads to proper G2/M progression. Collectively, our results reveal TOPK and PTEN as new players in CHFR mediated mitotic checkpoint.

Highlights

CHFR is a well defined mitotic checkpoint protein that delays entry into mitosis in response to stress [1]
Phosphorylation of PTEN is required for proper entry into mitosis as expression of non-phosphorylatable PTEN S380A mutant significantly reduced the mitotic cell population (Fig. 4g), which is similar to the observed phenotype upon CHFR expression. Taken together these results suggest that TOPK inactivates PTEN by phosphorylating S380 residue during mitosis, which leads to activation of Akt that is required for proper mitotic progression (Fig. 4h)
We demonstrated that CHFR ubiquitinates and regulates TOPK levels, which is essential for its checkpoint function

Summary

Introduction

CHFR is a well defined mitotic checkpoint protein that delays entry into mitosis in response to stress [1]. The role of CHFR in mitotic checkpoint is attributed to its function as an E3 ligase, which ubiquitinates and degrades its target proteins. CHFR is known to regulate the stability of very limited substrates such as Aurora A, Plk, Kif and PARP1, which are critical for proper mitotic transitions. In addition to its proteosomal substrates, CHFR was shown to regulate checkpoint in a proteosomal independent manner [2]. For instance ubiquitylation-dependent activation of p38 kinase but not proteasome dependent degradation by CHFR contributes to its checkpoint [3]. CHFR controls mitotic transitions by regulating the nuclear localization of cyclin B [4]

Methods

Results

Conclusion