Citron kinase - renaissance of a neglected mitotic kinase.

Pier Paolo D'Avino

doi:10.1242/jcs.200253

Abstract

Cell division controls the faithful segregation of genomic and cytoplasmic materials between the two nascent daughter cells. Members of the Aurora, Polo and cyclin-dependent (Cdk) kinase families are known to regulate multiple events throughout cell division, whereas another kinase, citron kinase (CIT-K), for a long time has been considered to function solely during cytokinesis, the last phase of cell division. CIT-K was originally proposed to regulate the ingression of the cleavage furrow that forms at the equatorial cortex of the dividing cell after chromosome segregation. However, studies in the last decade have clarified that this kinase is, instead, required for the organization of the midbody in late cytokinesis, and also revealed novel functions of CIT-K earlier in mitosis and in DNA damage control. Moreover, CIT-K mutations have recently been linked to the development of human microcephaly, and CIT-K has been identified as a potential target in cancer therapy. In this Commentary, I describe and re-evaluate the functions and regulation of CIT-K during cell division and its involvement in human disease. Finally, I offer my perspectives on the open questions and future challenges that are necessary to address, in order to fully understand this important and yet unjustly neglected mitotic kinase.

Highlights

The fascinating process of cell division is essential for growth, development and reproduction in many organisms
The initial but, later found to be incorrect, model positing a role for citron kinase (CIT-K) as a Rho effector that promotes the constriction of the actomyosin ring during cytokinesis (Madaule et al, 1998, 2000; Yamashiro et al, 2003), might have hindered efforts to further characterise the multiple roles and mechanisms of action of this important kinase (Fig. 1) because the cellular function of CIT-K was assumed to have been established, with it only playing an ancillary role in cytokinesis
I hope that this Commentary will serve to ‘rehabilitate’ and re-evaluate this important kinase, and eliminate the misconception that CIT-K is required for the constriction of the actomyosin ring − which is still present in the scientific community

Summary

Introduction

The fascinating process of cell division is essential for growth, development and reproduction in many organisms. Initial reports more than a decade ago indicated that CIT-K has a role in the contraction of the actomyosin ring by phosphorylating MRLC (Madaule et al, 1998, 2000; Yamashiro et al, 2003) These studies were solely on the basis of CIT-K overexpression and in vitro experiments, and were challenged by the findings that, in Drosophila, depletion or mutations of the sti gene caused failure of cytokinesis at a late stage, i.e. after completion of furrow ingression (D’Avino et al, 2004; Echard et al, 2004; Naim et al, 2004; Shandala et al, 2004). As the role of Ephrin/Eph signalling is established in

B Late telophase Aurora B

Conclusions and future perspectives