THE PROTEIN-TYROSINE-PHOSPHATASE SHP-2 NEGATIVELY REGULATES CILIARY NEUROTROPHIC FACTOR INDUCTION OF GENE-EXPRESSION

Ciliary neurotrophic factor, along with other neuropoietic cytokines, signals through the shared receptor subunit gp130 [1-3], leading to th e tyrosine phosphorylation of a number of substrates [4,5], including the transcription factors STAT1 and STAT3 and the protein tyrosine pho sphatase SHP-2 [6-8]. SHP-2 (also known as PTP1D, SHPTP2, Syp and PTP2 C) is a positive regulatory molecule required for the activation of th e mitogen-activated protein kinase pathway and the stimulation of gene expression in response to epidermal growth factor, insulin and platel et-derived growth factor stimulation [9-11]. We have previously shown that cytokines that signal via the gp130 receptor subunit activate tra nscription of the vasoactive intestinal peptide (VIP) gene through a 1 80 bp cytokine response element (CyRE) [12,13], To characterize the ro le of SHP-2 in the regulation of gp130-stimulated gene expression, we examined the regulation of the VIP CyRE in two systems that prevented ligand-dependent SHP-2 phosphorylation. Inhibition of SHP-2, either by mutating the tyrosine residue in gp130 that mediates the SHP-2 intera ction, or by expression of dominant-negative SHP-2, resulted in dramat ic increases in gp130-dependent gene expression, through the VIP CyRE and more specifically through multimerized STAT-binding sites, These d ata suggest that SHP-2 has a negative role in gp130 signaling by modul ating STAT-mediated transcriptional activation.