Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation.
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.
Toyo-oka
Kazuhito
K
Department of Genetic Disease Research and 2Department of Pharmacology, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan.
Mori
Daisuke
D
Yano
Yoshihisa
Y
Shiota
Masayuki
M
Iwao
Hiroshi
H
Goto
Hidemasa
H
Inagaki
Masaki
M
Hiraiwa
Noriko
N
Muramatsu
Masami
M
Wynshaw-Boris
Anthony
A
Yoshiki
Atsushi
A
Hirotsune
Shinji
S
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D020134:Catalytic Domain / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D018385:Centrosome / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007313:Insecta; D000074201:Katanin; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008938:Mitosis / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D008941:Spindle Apparatus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure
D002352:Carrier Proteins; C421108:NDEL1 protein, human; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4; D000251:Adenosine Triphosphatases; D000074201:Katanin