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 SH2-1313 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-Bbeta is specific to JAK2 and SH2-Bbeta or extends to other JAKs or other members of the SH2-1313 family. When SH2-1313 was overexpressed with JAK1 or JAK3, SH2-Bbeta failed to increase their activity. However, SH2-Bbeta bound to both and was tyrosyl-phosphorylated by JAK1. In contrast to SH2-Bbeta,6, 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 tyrosylphosphorylated 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-Bbeta specifically activates JAK2, 2) APS negatively regulates both JAK2 and JAK1, and 3) both SH2-Bbeta and APS may serve as adapter proteins for all three JAKs independent of any role they have in JAK activity.