Differential regulation of leukemia inhibitory factor-stimulated neuronal gene expression by protein phosphatases SHP-1 and SHP-2 through mitogen-activated protein kinase-dependent and -independent pathways

The neurally active cytokine leukemia inhibitory factor (LIF) signals throu gh a bipartite receptor complex composed of LIF receptor alpha (LIFR) and g p130. gp130 and LIFR contain consensus binding motifs for the protein tyros ine phosphatase SHP-2 surrounding tyrosines 118 and 115 (Y118 and Y115) of their cytoplasmic domains, respectively. These sites are necessary for maxi mal activation of mitogen-activated protein kinase (MAPK). Coexpression of catalytically inactive, but not wild-type, SHP-2 reduced LIFR- and gp130-me diated activation of MAPK up to 75%. Conversely, coexpression of the wild-t ype, but not catalytically inactive, SHP-1, a related phosphatase, reduced activity up to 80%, demonstrating that SHP-2 and SHP-1 have opposing effect s on the MAPK pathway. Mutation of Y115 of the cytoplasmic domain of LIFR e liminates receptor-mediated tyrosine phosphorylation of SHP-2. In contrast, SHP-1 association with gp130 and LIFR is constitutive and independent of Y 118 and Y115, respectively. SHP-1 has a positive regulatory role on LIF-sti mulated vasoactive intestinal peptide (VIP) reporter gene expression in neu ronal cells, whereas the effect of SHP-2 is negative. Furthermore, LIF-stim ulated MAPK activation negatively regulates this VIP reporter gene inductio n. SHP-2 also negatively regulates LIF-dependent expression of choline acet yltransferase, but this regulation could be dissociated from its effects on MAPK activation. These data indicate that SHP-1 and SHP-2 are important re gulators of LIF-dependent neuronal gene expression via both MAPK-dependent and -independent pathways.