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Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation

¹ Department of Genetic Disease Research and ² Department of Pharmacology, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan
³ Division of Biochemistry, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan
⁴ Experimental Animal Division, Department of Biological Systems, BioResource Center, RIKEN Tsukuba Institute, Ibaraki 305-0074, Japan
⁵ Division of Neuroscience, Research Center for Genomic Medicine, Saitama Medical School, Saitama 350-1241, Japan
⁶ Department of Pediatrics and ⁷ Institute of Human Genetics, School of Medicine, University of California, San Fransisco, San Francisco, CA 94143

Correspondence to Shinji Hirotsune: shinjih{at}med.osaka-cu.ac.jp

Protein phosphatase 4 catalytic subunit (PP4c) is a PP2A-related protein serine/threonine phosphatase with important functions in a variety of cellular processes, including microtubule (MT) growth/organization, apoptosis, and tumor necrosis factor signaling. In this study, we report that NDEL1 is a substrate of PP4c, and PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome. Targeted disruption of PP4c reveals disorganization of MTs and disorganized MT array. Loss of PP4c leads to an unscheduled activation of Cdk1 in interphase, which results in the abnormal phosphorylation of NDEL1. In addition, abnormal NDEL1 phosphorylation facilitates excessive recruitment of katanin p60 to the centrosome, suggesting that MT defects may be attributed to katanin p60 in excess. Inhibition of Cdk1, NDEL1, or katanin p60 rescues the defective MT organization caused by PP4 inhibition. Our work uncovers a unique regulatory mechanism of MT organization by PP4c through its targets Cdk1 and NDEL1 via regulation of katanin p60 distribution.

Abbreviations used in this paper: KLH, keyhole limpet hemocyanin; MEF, mouse embryonic fibroblast; MT, microtubule; PP4c, protein phosphatase 4 catalytic subunit.

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