The inhibition of interleukin-6-dependent STAT activation by mitogen-activated protein kinases depends on tyrosine 759 in the cytoplasmic tail of glycoprotein 130

Mitogen-activated protein (MAP) kinases stimulated by phorbol 13-myristate 12-acetate (PMA) have been shown to inhibit interleukin-6-induced activatio n of STAT3 (Sengupta, T. K., Talbot, E. S., Scherle, P. A., and Ivashkiv, L , B. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 11107-11112). In the present study we demonstrate that in addition to STAT3, also tyrosine phosphorylati on of STAT1, signal transducer gp130, and phosphotyrosine-phosphatase SHP2 underlies negative regulation by MAP kinases. Stimulation of Erks by basic fibroblast growth factor or a constitutively active mutant of Raf also led to down-regulation of STAT activity. Using chimeric receptor mutants we sho w that tyrosine 759 of glycoprotein 130 is crucial for the inhibitory effec t of MAP kinases, Inhibition is also dependent on gene transcription and tr anslation indicating that newly synthesized proteins are involved. Both PMA and basic fibroblast growth factor rapidly stimulate mRNA expression of th e suppressor of cytokine signaling-3 (SOCS-3) and this induction is strongl y reduced by an inhibitor of MAP kinase activation, Together with recent re sults demonstrating that SOCS-3 can bind in vitro to a phosphorylated tyros ine 759 peptide of glycoprotein 130 these data suggest SOCS-3 to be instrum ental in the inhibition of the Janus kinase/STAT pathway by MAP kinases.