Feed-forward mechanism of converting biochemical cooperativity to mitotic processes at the kinetochore plate.

ABSTRACT: The feed-forward mechanism is observed in some of the intracellular events, such as metabolic and transcriptional regulatory networks, but not in dynamic mitotic processes. Mammalian polo-like kinase 1 (Plk1) rapidly accumulates at centrosomes and kinetochores as cells enter mitosis. Plk1 function is spatially regulated through the targeting activity of the polo-box domain (PBD) that binds to a phosphoepitope generated by either cyclin dependent kinase 1 (Cdk1) (non-self-priming) or Plk1 itself (self-priming). "Non-self-priming and binding" is thought to ensure the orderly execution of cell cycle events. The physiological significance of the "self-priming and binding" is unknown. Using a pair of ELISA, here we demonstrated that mutations of the self-priming site of a kinetochore component, PBIP1/MLF1IP/KLIP1/CENP-50/CENP-U (PBIP1), to a Cdk1-dependent non-self-priming site abolished product-activated cooperativity in the formation of the Plk1-PBIP1 complex. Both PBD-dependent "two-dimensional" interaction with surface-restricted PBIP1 and subsequent phosphorylation of PBIP1 by anchored Plk1 were crucial to cooperatively generate the Plk1-PBIP1 complex. Highlighting the importance of this mechanism, failure in this process resulted in improper Plk1 recruitment to kinetochores, mitotic arrest, chromosome missegregation, and apoptosis. Thus, Plk1 PBD-dependent biochemical cooperativity is tightly coupled to mitotic events at the kinetochore plate through a product-activated, feed-forward mechanism. Given the critical role of self-priming and binding in the recruitment of Plk1 to surface-confined structures, such as centrosomes, kinetochores, and midbody, we propose that the observed feed-forward mechanism serves as a fundamental biochemical process that ensures dynamic nature of Plk1 localization to and delocalization from these subcellular locations.

SUBMITTER: Park JE 

PROVIDER: S-EPMC3100994 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature