Identification of SH2-Bβ as a potent cytoplasmic activator of the tyrosine kinase Janus kinase 2

L Rui, C Carter-Su - … of the National Academy of Sciences, 1999 - National Acad Sciences
L Rui, C Carter-Su
Proceedings of the National Academy of Sciences, 1999National Acad Sciences
Janus kinases (JAKs) are cytoplasmic tyrosine kinases critical for signaling by growth
hormone (GH) and many other ligands that bind to members of the cytokine receptor
superfamily. SH2-Bβ was previously identified as a JAK2-interacting protein that is tyrosyl
phosphorylated in response to GH and other cytokines that activate JAK2. In this study, we
examined whether SH2-Bβ alters the activity of JAK2. SH2-Bβ, when coexpressed with
JAK2, significantly increased the tyrosyl phosphorylation of JAK2 and multiple other cellular …
Janus kinases (JAKs) are cytoplasmic tyrosine kinases critical for signaling by growth hormone (GH) and many other ligands that bind to members of the cytokine receptor superfamily. SH2-Bβ was previously identified as a JAK2-interacting protein that is tyrosyl phosphorylated in response to GH and other cytokines that activate JAK2. In this study, we examined whether SH2-Bβ alters the activity of JAK2. SH2-Bβ, when coexpressed with JAK2, significantly increased the tyrosyl phosphorylation of JAK2 and multiple other cellular proteins and stimulated the kinase activity of JAK2 by ≈20-fold. Coexpression of SH2-Bβ with JAK2 dramatically increased tyrosyl phosphorylation of signal transducer and activator of transcription (Stat)5B and Stat3, physiological substrates of JAK2. SH2-Bβ(R555E) with a defective Src homology 2 domain was unable to stimulate JAK2 and JAK2-mediated tyrosyl phosphorylation of Stat5B and Stat3. More importantly, SH2-Bβ enhanced GH-induced tyrosyl phosphorylation of endogenous JAK2 and ligand-induced tyrosyl phosphorylation of Stat5B by endogenous JAK2. In contrast, SH2-Bβ did not potentiate the activation of other tyrosine kinases including the receptors for platelet-derived growth factor, epidermal growth factor, or nerve growth factor (TrkA), tyrosine kinases that also bind SH2-Bβ. These data demonstrate that SH2-Bβ is a potent cytoplasmic activator of JAK2 and is thereby expected to be an important cellular regulator of signaling by GH and other hormones and cytokines that activate JAK2.
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