Phosphorylation of KIF18A Alters Its Mitotic Function and Localization

Abstract

Kinesin motor proteins play important roles in intracellular transport, cell division, and cilia function. Eukaryotic cells express many kinesins (45 in mammals) to support these diverse cellular processes in cell cycle and cell type dependent manners. Of the 45 mammalian kinesins, 44 of them have identified sites of post-translational modification (PTM) within their enzymatic region, suggesting the activity of kinesins may be reversibly regulated. Our long-term goal is to investigate how kinesin function is controlled through these PTMs. We are currently investigating the effects of three previously identified phosphorylation sites (S244, S284, and S357) on the mitotic functions of KIF18A. KIF18A (kinesin-8) is a mammalian kinesin that suppresses the dynamics of microtubules to promote chromosome alignment during cell division. KIF18A is also known to play a role in kinetochore microtubule attachment and the metaphase to anaphase transition in some cell types. However, little is understood about how KIF18A is regulated to perform these various functions. Our data suggest that phosphorylation at S357 promotes the localization of KIF18A to non-kinetochore microtubules within the spindle. Additionally, mutation of S284 leads to accumulation of KIF18A at centrosomes, while a non-phosphorylatable substitution at S244 increases the time required to complete mitosis. Taken together this work indicates that phosphorylation of residues within KIF18A's enzymatic region are important for controlling its activity and localization during cell division.