YXXL motifs in SH2-Bbeta are phosphorylated by JAK2, JAK1, and platelet-derived growth factor receptor and are required for membrane ruffling.
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.
O'Brien
Karen B
KB
Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 49109-0622, USA.
Argetsinger
Lawrence S
LS
Diakonova
Maria
M
Carter-Su
Christin
C
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003599:Cytoskeleton / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; C492010:SH2B1 protein, rat; C115327:Sh2bpsm1 protein, mouse; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; C507905:Jak1 protein, mouse; C507906:Jak1 protein, rat; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2