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Molecular and Cellular Biology, November 2006, p. 8639-8654, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00816-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Identification of Yin-Yang Regulators and a Phosphorylation Consensus for Male Germ Cell-Associated Kinase (MAK)-Related Kinase{triangledown}

Zheng Fu,1 Katherine A. Larson,1 Raghu K. Chitta,3 Sirlester A. Parker,5 Benjamin E. Turk,5 Matthew W. Lawrence,1 Philipp Kaldis,6 Konstantin Galaktionov,7 Steven M. Cohn,2 Jeffrey Shabanowitz,3 Donald F. Hunt,3,4 and Thomas W. Sturgill1*

Departments of Pharmacology,1 Internal Medicine,2 Chemistry,3 Pathology, University of Virginia, Charlottesville, Virginia 22908,4 Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520,5 Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702,6 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 770307

Received 8 May 2006/ Returned for modification 12 July 2006/ Accepted 5 September 2006

MAK (male germ cell-associated protein kinase) and MRK/ICK (MAK-related kinase/intestinal cell kinase) are human homologs of Ime2p in Saccharomyces cerevisiae and of Mde3 and Pit1 in Schizosaccharomyces pombe and are similar to human cyclin-dependent kinase 2 (CDK2) and extracellular signal-regulated kinase 2 (ERK2). MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation. Herein, we establish that human CDK-related kinase CCRK (cell cycle-related kinase) is an activating T157 kinase for MRK, whereas active CDK7/cyclin H/MAT1 complexes phosphorylate CDK2 but not MRK. Protein phosphatase 5 (PP5) interacts with MRK in a complex and dephosphorylates MRK at T157 in vitro and in situ. Thus, CCRK and PP5 are yin-yang regulators of T157 phosphorylation. To determine a substrate consensus, we screened a combinatorial peptide library with active MRK. MRK preferentially phosphorylates R-P-X-S/T-P sites, with the preference for arginine at position –3 (P–3) being more stringent than for prolines at P–2 and P+1. Using the consensus, we identified a putative phosphorylation site (RPLT1080S) for MRK in human Scythe, an antiapoptotic protein that interacts with MRK. MRK phosphorylates Scythe at T1080 in vitro as determined by site-directed mutagenesis and mass spectrometry, supporting the consensus and suggesting Scythe as a physiological substrate for MRK.

* 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.

{triangledown} Published ahead of print on 5 September 2006.

Molecular and Cellular Biology, November 2006, p. 8639-8654, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00816-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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