Protein Tyrosine Phosphatase 1B Attenuates Growth Hormone-Mediated JAK2-STAT Signaling

Abstract

Protein tyrosine phosphatase-1B (PTP-1B) attenuates insulin, PDGF, EGF, and IGF-I signaling by dephosphorylating tyrosine residues located in the tyrosine kinase domain of the corresponding receptors. More recently, PTP-1B was shown to modulate the action of cytokine signaling via the nonreceptor tyrosine kinase JAK2. Transmission of the growth hormone (GH) signal also depends on JAK2, raising the possibility that PTP-1B modulates GH action. Consistent with this hypothesis, GH increased the abundance of tyrosine-phosphorylated JAK2 associated with a catalytically inactive mutant of PTP-1B. GH-induced JAK2 phosphorylation was greater in knockout (KO) than in wild-type (WT) PTP-1B embryonic fibroblasts and resulted in increased tyrosine phosphorylation of STAT3 and STAT5, while overexpression of PTP-1B reduced the GH-mediated activation of the acid-labile subunit gene. To evaluate the in vivo relevance of these observations, mice were injected with GH under fed and fasted conditions. As expected, tyrosine phosphorylation of JAK2 and STAT5 occurred readily in the livers of fed WT mice and was almost completely abolished during fasting. In contrast, resistance to the action of GH was severely impaired in the livers of fasted KO mice. These results indicate that PTP-1B regulates GH signaling by reducing the extent of JAK2 phosphorylation and suggest that PTP-1B is essential for limiting the action of GH during metabolic stress such as fasting.

ACKNOWLEDGMENTS

We thank A. F. Parlow and the National Hormone and Pituitary Program for hGH, Suhad Ali for 293LA cells, W. Baumbach for GHR antibodies, Yosé ChÂteauvert-Lavoie for excellent technical help, and Charity McNamara for performing the transfection assay.

F.G. is the recipient of a Human Frontier Science Program postdoctoral fellowship. N.D. is the recipient of a Canadian Institutes of Health Research doctoral award. This work was supported by a Cancer Research Society Operating Grant to M.L.T. and NIH grant 2R01 DK051624 to Y.R.B.

F. Gu and N. Dubé are joint first authors.