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Papers In Press, published online ahead of print March 19, 2002
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185
Corresponding Author: gwhart{at}jhmi.edu
Previously, we reported that c-Myc is glycosylated by O-linked N-acetylglucosamine at Thr58, a known phosphorylation site and a mutational hot spot in lymphomas. In this paper, we describe the production and characterization of two Thr58 site-specific antibodies, and use them to examine the modification of Thr58 in living cells. One antibody specifically reacts with the Thr58-glycosylated form of c-Myc and the other reacts only with unmodified Thr58 in c-Myc. Using these antibodies together with a commercial anti-Thr58-phosphorylated c-Myc antibody, we simultaneously detected three forms of c-Myc (Thr58-unmodified, -phosphorylated, and -glycosylated). It has been reported that Thr58 phosphorylation is dependent on a prior phosphorylation of Ser62. Mutagenesis of Ser62 to Ala showed a marked decrease of Thr58 phosphorylation and a marked increase of Thr58 glycosylation. Growth inhibition of HL60 cells by serum starvation increases Thr58 glycosylation and correspondingly decreases its phosphorylation. Serum stimulation has the opposite effect upon the modification status of Thr58. A candidate kinase responsible for Thr58 phosphorylation is the glycogen synthase kinase 3 (GSK3). Lithium, a competitive inhibitor of GSK3, decreased Thr58 phosphorylation and increased its glycosylation. Finally, we show that the Thr58-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 Ser62 and Thr58, and alternative glycosylation/phosphorylation of Thr58 together regulate the myriad functions of c-Myc in cells.
J. Biol. Chem, 10.1074/jbc.M201729200
Submitted on February 20, 2002
Revised on March 14, 2002
Accepted on March 19, 2002
Dynamic interplay between O-glycosylation and O-phosphorylation of nucleocytoplasmic proteins. Alternative glycosylation/phosphorylation of Thr58, a known mutational hot spot of c-Myc in lymphomas, is regulated by mitogens
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