Growth hormone stimulates the tyrosine kinase activity of JAK2 and inducestyrosine phosphorylation of insulin receptor substrates and Shc in rat tissues

GH stimulates the tyrosine phosphorylation of various cellular polypeptides , including the GH receptor itself, in an early part of the intracellular r esponse. Some of these phosphorylations are catalyzed by a GH receptor-asso ciated kinase identified as JAK2, a member of the Janus family of tyrosine kinases. In cultured cells, GH stimulates the tyrosine phosphorylation of i nsulin receptor substrate-1 (IRS-1), IRS-2, and Shc. This study investigate d whether GH could cause the tyrosine phosphorylation of IRSs and Shc prote ins in fasted rat tissues in vivo. GH was administered to fasted Wistar rat s via a portal vein, and extracts of different tissues were immunoprecipita ted with specific antibodies. GH increased the tyrosine phosphorylation of IRS-1, IRS-8, JAK2, and Shc proteins in the liver, heart, kidney, muscle, a nd adipose tissue of rats. The roles of these substrates as signaling molec ules for GH were further demonstrated by the finding that GH stimulated the association of IRS-1/2 with phosphatidylinositol 3-kinase, Grb2, and phosp hotyrosine phosphatase and of Shc with Grb2. The correlation between JAK2 t yrosyl phosphorylation and IRS-1 tyrosyl phosphorylation in response to GH together with the results of the in vitro tyrosine kinase assay are consist ent with the hypothesis that JAK2 may mediate GH-induced phosphorylation of IRS-1.