DESCRIPTION The src homology 2 (SH2) domain-containing protein tyrosine phosphatase SHP-2 has been implicated as an important positive regulator of several mitogenic signaling pathways. SHP-2 has more recently been shown to be tyrosine phosphorylated and recruited to the gp130/LIFR subunits of the CNTF receptor complex upon stimulation with ciliary neurotrophic factor (CNTF). CNTF does not, however, have a proliferative effect on responsive cells, but rather enhances the survival and differentiation of sympathetic, motor, and sensory neurons. In the Preliminary Studies section the applicants demonstrate that expression of an interfering SH2 domain mutant of SHP-2 in a neuroblastoma cell line increases CNTF induction of a vasoactive intestinal peptide (VIP) reporter gene and in cultures of sympathetic neurons results in an upregulation of endogenous VIP, substance P (SP) and choline acetyltransferase (ChAT) gene expression. They also found in parallel studies that expression of the SHP-2 interfering mutant abolishes CNTF induction of c-Fos protein levels. Members of the CNTF family of cytokines transmit their signal by activating signaling pathways involving both STAT and Fos-Jun (AP-1) transcription factors and activated STAT is necessary for induction of the VIP gene. Taken together, these data indicate that SHP-2 has dual and opposing roles in a signaling cascade triggered by the same ligand, as illustrated by its negative function in induction of VIP, SP and ChAT levels and positive function in induction of c-Fos levels. In this proposal they will examine in detail the pathways that are activated by neurocytokines such as CNTF and define the molecular mechanisms of how SHP-2 regulates these parallel signaling pathways.