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Vol. 19, Issue 4, 1317-1327, April 2008

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Roles of Greatwall Kinase in the Regulation of Cdc25 Phosphatase

Yong Zhao^*, Olivier Haccard, Ruoning Wang, Jiangtao Yu^*, Jian Kuang, Catherine Jessus, and Michael L. Goldberg^*

*Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853-2703; Centre Nationale de la Recherche Scientifique, UMR7622, Université Pierre et Marie Curie, Biologie du Développement, 75252 Paris, France; and Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030

Submitted November 2, 2007; Revised December 26, 2007; Accepted January 8, 2008
Monitoring Editor: Mark Solomon

We previously reported that immunodepletion of Greatwall kinase prevents Xenopus egg extracts from entering or maintaining M phase due to the accumulation of inhibitory phosphorylations on Thr14 and Tyr15 of Cdc2. M phase–promoting factor (MPF) in turn activates Greatwall, implying that Greatwall participates in an MPF autoregulatory loop. We show here that activated Greatwall both accelerates the mitotic G2/M transition in cycling egg extracts and induces meiotic maturation in G2-arrested Xenopus oocytes in the absence of progesterone. Activated Greatwall can induce phosphorylations of Cdc25 in the absence of the activity of Cdc2, Plx1 (Xenopus Polo-like kinase) or mitogen-activated protein kinase, or in the presence of an activator of protein kinase A that normally blocks mitotic entry. The effects of active Greatwall mimic in many respects those associated with addition of the phosphatase inhibitor okadaic acid (OA); moreover, OA allows cycling extracts to enter M phase in the absence of Greatwall. Taken together, these findings support a model in which Greatwall negatively regulates a crucial phosphatase that inhibits Cdc25 activation and M phase induction.

Address correspondence to: Michael L. Goldberg (mlg11{at}cornell.edu).

Abbreviations used: CamKII, Ca²⁺/calmodulin kinase II; CDK, cyclin-dependent kinase; CHX, cycloheximide; CSF, cytostatic factor; GVBD, germinal vesicle breakdown; KD, kinase dead; MAPK, mitogen-activated protein kinase; MPF, mitosis-promoting factor; OA, okadaic acid; PKA, protein kinase A; PP2A, protein phosphatase 2A; Ros, roscovitine; WT, wild type.