Signaling-dependent Phosphorylation of Mitotic Centromere-associated Kinesin Regulates Microtubule Depolymerization and Its Centrosomal Localization

Abstract

Although PAK1 regulates cytoskeleton and microtubule dynamics, its role in controlling the functions of MCAK remains unknown. PAK1 phosphorylates MCAK and thereby regulates both its localization and function. MCAK is a cognate substrate of PAK1. This study provides a novel mechanistic insight into PAK1 regulation of MCAK functions. Although p21-activated kinase 1 (PAK1) and microtubule (MT) dynamics regulate numerous fundamental processes including cytoskeleton remodeling, directional motility, and mitotic functions, the significance of PAK1 signaling in regulating the functions of MT-destabilizing protein mitotic centromere-associated kinesin (MCAK) remains unknown. Here we found that MCAK is a cognate substrate of PAK1 wherein PAK1 phosphorylates MCAK on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that PAK1 phosphorylation of MCAK on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes, respectively, in the mammalian cells.