SH2-B Family Members Differentially Regulate JAK Family Tyrosine Kinases

Abstract

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-␥. Previously, we identified SH2-B␤ 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␤ is specific to JAK2 and SH2-B␤ or extends to other JAKs or other members of the SH2-B␤ family. When SH2-B␤ was overexpressed with JAK1 or JAK3, SH2-B␤ failed to increase their activity. However, SH2-B␤ bound to both and was tyrosyl-phosphorylated by JAK1. In contrast to SH2-B␤, APS decreased tyrosyl phosphorylation of GHstimulated 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-␥. These results suggest that 1) SH2-B␤ specifically activates JAK2, 2) APS negatively regulates both JAK2 and JAK1, and 3) both SH2-B␤ and APS may serve as adapter proteins for all three JAKs independent of any role they have in JAK activity.

Preclinical Characterization of GLPG0634, a Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

“…A differential tyrosine phosphorylation status can give rise to different IC 50 values as exemplified for the non-versus monoor diphosphorylated forms of the TYK2 kinase domain (29). Third, differential negative or positive feedback mechanisms for JAK1-versus JAK2-dependent signaling by means of phosphatases, members of the SOCS or SH2B families, can have a different impact on the amplitude and kinetics of JAK enzyme activity and signaling output (30)(31)(32)(33). Finally, different small molecules might induce subtle changes in the three-dimensional space of the ATPbinding pockets of the JAKs, leading to differential kinase activity and/or protein-protein interactions.…”

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

“…Sh2b1 mediates activation of various kinases and may function in cytokine and growth factor receptor signaling and cellular. A recent study found that SH2-B b specifically activates JAK2 and functions as an adapter protein that cross-links actin filaments, leading to modulation of cellular responses in response to JAK2 activation (41,42). Another study shows an essential role of SH2-B b in the activation of the Src kinase and the resulting mitogenic response, causing phenotypic cell transformation involving the Src substrate STAT3 (43).…”

SH2B1 regulation of energy balance, body weight, and glucose metabolism

“…SH2B2 binds via both its SH2 domain and non-SH2 domain regions to JAK2, and its SH2 domain binds to phospho-Tyr 813 of JAK2 [16,146] . Unlike SH2B1, SH2B2 is unable to activate, or only slightly activates, JAK2 [61,146] . Multiple cytokines, including interferon-γ, EPO, leukemia inhibitor factor, granulocyte-macrophage colony stimulating factor, interleukin-5 (IL-5) and IL-3, stimulate tyrosine phosphorylation of SH2B2, presumably through JAK family members [135,145,147] .…”

“…SH2B2 regulates cytokine signaling and immune response Like SH2B1, SH2B2 binds via its SH2 domain to JAK1, JAK2 and JAK3, and is tyrosyl phosphorylated by these kinases [61,145] . SH2B2 binds via both its SH2 domain and non-SH2 domain regions to JAK2, and its SH2 domain binds to phospho-Tyr 813 of JAK2 [16,146] .…”

“…Knockdown of SH2B1 increases EPO-stimulated tyrosine phosphorylation of EPO receptors, JAK2, and ERK1/2, raising the possibility that SH2B1 may negatively regulate EPO signaling [60] . SH2B1 binds to JAK1, JAK2 and JAK3, but it only stimulates JAK2, but not JAK1 and JAK3, kinase activity [61] . Both JAK1 and JAK2 are able to phosphorylate SH2B1 on Tyr 439 and Tyr…”