Regulation of p27Kip1phosphorylation and G1 cell cycle progression by protein phosphatase PPM1G.
The cell cycle, an essential process leading to the cell division, is stringently controlled by the key cell cycle regulators, cyclin-CDK complexes, whose activity is further regulated by a variety of mechanisms. p27Kip1is a cyclin-CDK inhibitor that arrests the cell cycle at the G1 phase by blocking the activation of cyclin E-CDK2 complex, preventing the improper entry to the cell cycle. Dysfunction of p27 has been frequently observed in many types of human cancers, resulting from p27 protein degradation and cytoplasmic mislocalization, which are highly regulated by the phosphorylation status of p27. Although the kinases that phosphorylate p27 have been extensively studied, phosphatases that dephosphorylate p27 remain to be elucidated. By using genomic phosphatase screening, we identified a PPM family phosphatase, PPM1G, which could reduce p27 phosphorylation at T198. We further confirmed that PPM1G is a novel p27 phosphatase by demonstrating that PPM1G can interact with and dephosphorylate p27 in cells andin vitro. Functionally, ectopic expression of PPM1G enhanced p27 protein stability and delayed cell cycle progression from G1 to S phase. In accordance, knockdown of PPM1G accelerated p27 degradation during G1 phase and rendered cells resistant to the cell cycle arrest induced by serum deprivation. Mechanistically, PPM1G inhibited the interaction of p27 to 14-3-3θ, a chaperone protein that facilitates p27 nuclear export. Knockdown of PPM1G promoted the cytoplasmic localization of p27. Taken together, our studies identified PPM1G as a novel regulator of p27 that dephosphorylates p27 at T198 site and, together with p27 kinases, PPM1G controls cell cycle progression by maintaining the proper level of p27 protein.
Department of Molecular Physiology and Biophysics, Baylor College of MedicineHouston, TX 77030, USA; Michael E. DeBakey Department of Surgery, Baylor College of MedicineHouston, TX 77030, USA.
Chuang
C
Sun
Michael E. DeBakey Department of Surgery, Baylor College of MedicineHouston, TX 77030, USA; Department of Molecular & Cellular Biology, Baylor College of MedicineHouston, TX 77030, USA; Life Sciences Institute and Innovation Center for Cell Signaling, Zhejiang UniversityHangzhou, Zhejiang 310058, China.
Gaohang
G
Wang
Michael E. DeBakey Department of Surgery, Baylor College of MedicineHouston, TX 77030, USA; Department of Molecular & Cellular Biology, Baylor College of MedicineHouston, TX 77030, USA; Present address: Nature Reviews JournalsPorters South, 4 Crinan Street, London, N1 9XW, United Kingdom.
Katharine H
KH
Wrighton
Department of Molecular Physiology and Biophysics, Baylor College of Medicine Houston, TX 77030, USA.
Han
H
Lin
Department of Biochemistry and Molecular Biology, Baylor College of Medicine Houston, TX 77030, USA.
Zhou
Z
Songyang
Department of Molecular Physiology and Biophysics, Baylor College of MedicineHouston, TX 77030, USA; Michael E. DeBakey Department of Surgery, Baylor College of MedicineHouston, TX 77030, USA; Department of Molecular & Cellular Biology, Baylor College of MedicineHouston, TX 77030, USA; Life Sciences Institute and Innovation Center for Cell Signaling, Zhejiang UniversityHangzhou, Zhejiang 310058, China.
Xin-Hua
XH
Feng
Michael E. DeBakey Department of Surgery, Baylor College of Medicine Houston, TX 77030, USA.
Xia
X
Lin
PPM1G; cell cycle; p27; protein phosphatase