SH2-B family members differentially regulate JAK family tyrosine kinases.
Activation of JAK tyrosine kinases is an essential step in cell signaling by multiple hormones, cytokines, and growth factors, including growth hormone (GH) and interferon-gamma. Previously, we identified SH2-B beta as a potent activator of JAK2 (Rui, L., and Carter-Su, C. (1999) Proc. Natl. Acad. Sci. U.S.A. 96, 7172-7177). Here, we investigated whether the activation of JAK2 by SH2-B beta is specific to JAK2 and SH2-B beta or extends to other JAKs or other members of the SH2-B beta family. When SH2-B beta was overexpressed with JAK1 or JAK3, SH2-B beta failed to increase their activity. However, SH2-B beta bound to both and was tyrosyl-phosphorylated by JAK1. In contrast to SH2-B beta, APS decreased tyrosyl phosphorylation of GH-stimulated JAK2 as well as Stat5B, a substrate of JAK2. APS also decreased tyrosyl phosphorylation of JAK1, but did not affect the activity or tyrosyl phosphorylation of JAK3. Overexpressed APS bound to and was tyrosyl-phosphorylated by all three JAKs. Consistent with these data, in 3T3-F442A adipocytes, endogenous APS was tyrosyl-phosphorylated in response to GH and interferon-gamma. These results suggest that 1) SH2-B beta specifically activates JAK2, 2) APS negatively regulates both JAK2 and JAK1, and 3) both SH2-B beta and APS may serve as adapter proteins for all three JAKs independent of any role they have in JAK activity.
O'Brien
Karen B
KB
Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622, USA.
O'Shea
John J
JJ
Carter-Su
Christin
C
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D051379:Mice; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; C518910:SH2B1 protein, human; C115327:Sh2bpsm1 protein, mouse; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3