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Molecular and Cellular Biology, July 2005, p. 6047-6064, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6047-6064.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation of a Nuclear Cdc2-Related Kinase within a Mitogen-Activated Protein Kinase-Like TDY Motif by Autophosphorylation and Cyclin-Dependent Protein Kinase-Activating Kinase

Zheng Fu,1 Melanie J. Schroeder,2 Jeffrey Shabanowitz,2 Philipp Kaldis,3 Kasumi Togawa,4 Anil K. Rustgi,4 Donald F. Hunt,2,5 and Thomas W. Sturgill1*

Departments of Pharmacology and Internal Medicine,1 Chemistry,2 Pathology, University of Virginia, Charlottesville, Virginia, 22908,5 Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702,3 Division of Gastroenterology, Departments of Medicine and Genetics, Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 191044

Received 13 December 2004/ Returned for modification 21 January 2005/ Accepted 4 April 2005

Male germ cell-associated kinase (MAK) and intestinal cell kinase (ICK) are nuclear Cdc2-related kinases with nearly identical N-terminal catalytic domains and more divergent C-terminal noncatalytic domains. The catalytic domain is also related to mitogen-activated protein kinases (MAPKs) and contains a corresponding TDY motif. Nuclear localization of ICK requires subdomain XI and interactions of the conserved Arg-272, but not kinase activity or, surprisingly, any of the noncatalytic domain. Further, nuclear localization of ICK is required for its activation. ICK is activated by dual phosphorylation of the TDY motif. Phosphorylation of Tyr-159 in the TDY motif requires ICK autokinase activity but confers only basal kinase activity. Full activation requires additional phosphorylation of Thr-157 in the TDY motif. Coexpression of ICK with constitutively active MEK1 or MEK5 fails to increase ICK phosphorylation or activity, suggesting that MEKs are not involved. ICK and MAK are related to Ime2p in budding yeast, and cyclin-dependent protein kinase-activating kinase Cak1p has been placed genetically upstream of Ime2p. Recombinant Cak1p phosphorylates Thr-157 in the TDY motif of recombinant ICK and activates its activity in vitro. Coexpression of ICK with wild-type CAK1 but not kinase-inactive CAK1 in cells also increases ICK phosphorylation and activity. Our studies establish ICK as the prototype for a new group of MAPK-like kinases requiring dual phosphorylation at TDY motifs.

* Corresponding author. Mailing address: Department of Pharmacology, University of Virginia School of Medicine, 1300 Jefferson Park Avenue, Charlottesville, VA 22908-0735. Phone: (434) 924-9191. Fax: (434) 924-5207. E-mail: Thomas_Sturgill{at}virginia.edu.

Molecular and Cellular Biology, July 2005, p. 6047-6064, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6047-6064.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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