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Originally published In Press as doi:10.1074/jbc.M201729200 on March 19, 2002

J. Biol. Chem., Vol. 277, Issue 21, 19229-19235, May 24, 2002
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Dynamic Interplay between O-Glycosylation and O-Phosphorylation of Nucleocytoplasmic Proteins
ALTERNATIVE GLYCOSYLATION/PHOSPHORYLATION OF THR-58, A KNOWN MUTATIONAL HOT SPOT OF c-Myc IN LYMPHOMAS, IS REGULATED BY MITOGENS*

Kazuo KamemuraDagger , Bradley K. Hayes§, Frank I. Comer, and Gerald W. Hart||

From the Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185

Previously, we reported that c-Myc is glycosylated by O-linked N-acetylglucosamine at Thr-58, a known phosphorylation site and a mutational hot spot in lymphomas. In this paper, we describe the production and characterization of two Thr-58 site-specific antibodies and use them to examine the modification of Thr-58 in living cells. One antibody specifically reacts with the Thr-58-glycosylated form of c-Myc, and the other reacts only with unmodified Thr-58 in c-Myc. Using these antibodies together with a commercial anti-Thr-58-phosphorylated c-Myc antibody, we simultaneously detected three forms of c-Myc (Thr-58-unmodified, -phosphorylated, and -glycosylated). It has been reported that Thr-58 phosphorylation is dependent on a prior phosphorylation of Ser-62. Mutagenesis of Ser-62 to Ala showed a marked decrease of Thr-58 phosphorylation and a marked increase of Thr-58 glycosylation. Growth inhibition of HL60 cells by serum starvation increases Thr-58 glycosylation and correspondingly decreases its phosphorylation. Serum stimulation has the opposite effect upon the modification status of Thr-58. A candidate kinase responsible for Thr-58 phosphorylation is the glycogen synthase kinase 3 (GSK3). Lithium, a competitive inhibitor of GSK3, decreased Thr-58 phosphorylation and increased its glycosylation. Finally, we show that the Thr-58-phosphorylated form of c-Myc predominantly accumulates in the cytoplasm rather than the nucleus upon inhibition of proteasome activity. These data suggest that hierarchical phosphorylation of Ser-62 and Thr-58 and alternative glycosylation/phosphorylation of Thr-58 together regulate the myriad functions of c-Myc in cells.

* This study was supported by NCI, National Institutes of Health Grant CA42486 (to G. W. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Fellow of Japan Society for Promotion of Science Postdoctoral Fellowships for Research Abroad 2000.

§ Present address: University of California at San Diego, CMM-East, Rm. 1088, 9500 Gilman Dr., La Jolla, CA 92093-0687.

Present address: Laboratory of Cellular and Molecular Biology, NCI, National Institutes of Health, 37 Convent Dr., MSC 4255, Bldg. 37, Rm. 1C08, Bethesda, MD 20892-4255.

|| To whom correspondence should be addressed: Dept. of Biological Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205-2185. Tel.: 410-614-5993; Fax: 410-614-8804; E-mail: gwhart@jhmi.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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