SH2-B Family Members Differentially Regulate JAK Family Tyrosine Kinases
pmid: 11751854
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.
- National Institute of Health Pakistan
- University of Michigan–Ann Arbor United States
- University of Michigan–Flint United States
- National Institutes of Health United States
DNA, Complementary, Janus Kinase 3, 3T3 Cells, Janus Kinase 1, Janus Kinase 2, Protein-Tyrosine Kinases, Precipitin Tests, Gene Expression Regulation, Enzymologic, Cell Line, Enzyme Activation, Mice, Proto-Oncogene Proteins, COS Cells, Animals, Humans, Phosphorylation, Carrier Proteins, Adaptor Proteins, Signal Transducing, Plasmids, Protein Binding
DNA, Complementary, Janus Kinase 3, 3T3 Cells, Janus Kinase 1, Janus Kinase 2, Protein-Tyrosine Kinases, Precipitin Tests, Gene Expression Regulation, Enzymologic, Cell Line, Enzyme Activation, Mice, Proto-Oncogene Proteins, COS Cells, Animals, Humans, Phosphorylation, Carrier Proteins, Adaptor Proteins, Signal Transducing, Plasmids, Protein Binding
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