INTERACTION OF GROWTH HORMONE-ACTIVATED STATS WITH SH2-CONTAINING PHOSPHOTYROSINE PHOSPHATASE SHP-1 AND NUCLEAR JAK2 TYROSINE KINASE

Growth hormone (GH) rapidly stimulates tyrosine phosphorylation follow ed by serine/threonine phosphorylation of multiple cytoplasmic STAT tr anscription factors, including one, STAT5b, that is uniquely responsiv e to the temporal pattern of plasma GH stimulation in rat liver and is proposed to play a central role in the activation of male-expressed l iver genes by GH pulses in vivo (Waxman, D, J,, Bam, P. A., Park, S. H ., and Choi, H. K. (1995) J. Biol. Chem. 270, 13262-13270). We now sho w that JAK2, the GH receptor-associated tyrosine kinase, is present bo th in the cytosol and in the nucleus in cultured liver cells and in ra t liver in vivo and that GH-activated STAT3 but not STAT5b becomes ass ociated with nuclear JAK2. GH is also shown to activate by 3-4-fold SH P-1, a phosphotyrosine phosphatase that contains two src homology 2 (S H2) domains. GI-I also induces nuclear translocation and binding of SH P-1 to tyrosine-phosphorylated STAT5b, suggesting that this GH-activat ed phosphatase may play a role in dephosphorylation leading to deactiv ation of nuclear STAT5b following the termination of a plasma GH pulse in male rat Liver in vivo, No such association of SHP-1 with GH-activ ated STATE was detected, a finding that could help explain the marked desensitization of STAT3, but not STAT5b, to subsequent GH pulses foll owing an initial GH activation event.