Decisive Role in Cell Division Identified for Centrosomal Protein

The answer to an elusive question about signaling in chromosome distribution and separation has been provided by the discovery of a key role for a centrosomal protein kinase. The kinase also has potential importance as a new candidate among cell division factors being targeted in the development of drug treatments for cancer.

The study, headed by principal researchers Joan Roig, PhD, at the Institute for Research in Biomedicine (IRB Barcelona; Barcelona, Spain) and Isabelle Vernos, PhD, at the Center for Genomic Regulation (CRG; Barcelona, Spain) highlights the protein kinase Nek9 as an essential and decisive factor in a pathway involved in ensuring efficient and accurate movement of chromosomes during cell division. γ-tubulin recruitment to and accumulation at the centrosome during the centrosome maturation stage of mitosis is known to depend on the adaptor protein NEDD1/GCP-WD and to be controlled by the kinase Plk1. Surprisingly, and although Plk1 binds and phosphorylates NEDD1 at multiple sites, the mechanism by which this kinase promotes centrosomal recruitment of γ-tubulin has remained elusive. Using Xenopus egg extracts and mammalian cells, the scientists found that Nek9, a kinase required for normal mitotic progression and spindle organization, phosphorylates NEDD1, driving its recruitment and thereby that of γ-tubulin to the centrosome. This role of Nek9 requires its activation by Plk1-dependent phosphorylation.



Errors in chromosome distribution cause many spontaneous miscarriages, some genetic defects such as trisomies, and are related to the development of tumors. Nek9 exerts its action between two molecules, Plk1 and Eg5, of interest as antitumoral agents and for which inhibitors are already in advanced stages of clinical trials. Nek9 could well be added to the list of cell division target candidates. “Through this study we demonstrate that a fourth family of proteins, namely NIMA and specifically Nek9, exert functions in cell division as important as those undertaken by the widely studied CDK (cdk1), Polo (Plk1) and Aurora (Aurora A and B) kinases”, explains Dr. Roig. “Without Nek9 the spindle would not form properly and cell division would be hindered, the cells would die or cause aneuploidies, with unequal distribution of chromosomes, an event that is common in tumors,” explains Dr. Vernos. The pharmaceutical industry is currently testing new drugs that inhibit Plk1, Eg5, and Aurora. “We are doing double-edged work: we describe how proteins involved in the initial stages of cell division are related in time and space, and in parallel we highlight the possible therapeutic tools, whether markers of disease or antimitotic agents, that can stop division and tumor growth”, says Dr. Roig.

The findings were published July 19, 2012, in the journal Current Biology.

Related Links:
Institute for Research in Biomedicine, Barcelona
Center for Genomic Regulation