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Originally published In Press as doi:10.1074/jbc.M210765200 on January 27, 2003

J. Biol. Chem., Vol. 278, Issue 14, 11970-11978, April 4, 2003
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YXXL Motifs in SH2-Bbeta Are Phosphorylated by JAK2, JAK1, and Platelet-derived Growth Factor Receptor and Are Required for Membrane Ruffling*

Karen B. O'BrienDagger , Lawrence S. Argetsinger, Maria Diakonova, and Christin Carter-Su§

From the Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 49109-0622

SH2-Bbeta binds to the activated form of JAK2 and various receptor tyrosine kinases. It is a potent stimulator of JAK2, is required for growth hormone (GH)-induced membrane ruffling, and increases mitogenesis stimulated by platelet-derived growth factor (PDGF) and insulin-like growth factor I. Its domain structure suggests that SH2-Bbeta may act as an adapter protein to recruit downstream signaling proteins to kinase·SH2-Bbeta complexes. SH2-Bbeta is tyrosyl-phosphorylated in response to GH and interferon-gamma , stimulators of JAK2, as well as in response to PDGF and nerve growth factor. To begin to elucidate the role of tyrosyl phosphorylation in the function of SH2-Bbeta , we used phosphopeptide mapping, mutagenesis, and a phosphotyrosine-specific antibody to identify Tyr-439 and Tyr-494 in SH2-Bbeta as targets of JAK2 both in vitro and in intact cells. SH2-Bbeta lacking Tyr-439 and Tyr-494 inhibits GH-induced membrane ruffling but still activates JAK2. We provide evidence that JAK1, like JAK2, phosphorylates Tyr-439 and Tyr-494 in SH2-Bbeta and that PDGF receptor phosphorylates SH2-Bbeta on Tyr-439. Therefore, phosphorylated Tyr-439 and/or Tyr-494 in SH2-Bbeta may provide a binding site for one or more proteins linking cytokine receptor·JAK2 complexes and/or receptor tyrosine kinases to the actin cytoskeleton.

* This research was supported in part by National Institutes of Health (NIH) Grant RO1-DK54222 and by the Juvenile Diabetes Research Foundation Center for the Study of Complications of Diabetes. DNA sequencing was carried out with the support of the Cellular and Molecular Biology Core of the Michigan Diabetes Research and Training Center (NIH Grant P60-DK20572) and the University of Michigan Comprehensive Cancer Center (NIH Grant P30-CA46592).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 Supported by a predoctoral fellowship from the Cancer Biology Training Program (Nancy Newton Loeb Fund) of the University of Michigan Comprehensive Cancer Center and a student in the Cellular and Molecular Biology Graduate Program at the University of Michigan.

§ To whom correspondence should be addressed: Dept. of Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109-0622. Tel.: 734-763-2561; Fax: 734-647-9523; E-mail: cartersu@umich.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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