Phospho-regulation of HsCdc14A By Polo-like kinase 1 is essential for mitotic progression.
Chromosome segregation in mitosis is orchestrated by dynamic interactions between spindle microtubules and centromeres, which in turn are governed by protein kinase- and phosphatase-signaling cascades. Previous studies showed that overexpression of human phosphatase HsCdc14A, an antagonist of cyclin-dependent kinase 1, affects several aspects of cell division. However, the molecular mechanism underlying HsCdc14A regulation in mitosis has remained elusive. Here we show that HsCdc14A activity is regulated by an auto-inhibitory mechanism via its intra-molecular association. Our biochemical study demonstrated that Polo-like kinase 1 (PLK1) interacts with and phosphorylates HsCdc14A. This phosphorylation partially releases the auto-inhibition of HsCdc14A judged by its phosphatase activity in vitro. To examine the functional relevance of such phospho-regulation of HsCdc14A in vivo, a phospho-mimicking mutant of HsCdc14A was expressed in HeLa cells. Importantly, overexpression of the phospho-mimicking mutants caused aberrant chromosome alignment with a prometaphase delay, suggesting the temporal regulation of HsCdc14A activity is critical for orchestrating mitotic events. Given the fact that HsCdc14A forms an intra-molecular association and PLK1-mediated phospho-regulation promotes HsCdc14A phosphatase activity, we propose that PLK1-HsCdc14A interaction provides a temporal regulation of HsCdc14A in chromosome segregation during mitosis.
Yuan
Kai
K
Division of Cellular Dynamics, Hefei National Laboratory and Chinese University of Science & Technology, Hefei 230027, China; Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310.
Hu
Haiying
H
Division of Cellular Dynamics, Hefei National Laboratory and Chinese University of Science & Technology, Hefei 230027, China; Department of Endocrinology and Metabolism, Hua Shan Hospital, Fudan University School of Medicine, Shanghai 200040, China, and.
Guo
Zhen
Z
Division of Cellular Dynamics, Hefei National Laboratory and Chinese University of Science & Technology, Hefei 230027, China; Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310.
Fu
Guosheng
G
Division of Cellular Dynamics, Hefei National Laboratory and Chinese University of Science & Technology, Hefei 230027, China.
Shaw
Andrew P
AP
Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310.
Hu
Renming
R
Department of Endocrinology and Metabolism, Hua Shan Hospital, Fudan University School of Medicine, Shanghai 200040, China, and. Electronic address: renminghu@fudan.edu.cn.
Yao
Xuebiao
X
Division of Cellular Dynamics, Hefei National Laboratory and Chinese University of Science & Technology, Hefei 230027, China; Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310. Electronic address: yaoxb@ustc.edu.cn.
D018797:Cell Cycle Proteins / Q000502:physiology*; D020090:Chromosome Segregation; D006801:Humans; D008938:Mitosis; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C120902:CDC14A protein, human