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 through a bipartite receptor complex composed of LIF receptor alpha (LIFR) and gp130. gp130 and LIFR contain consensus binding motifs for the protein tyrosine phosphatase SHP-2 surrounding tyrosines 118 and 115 (Y118 and Y115) of their cytoplasmic domains, respectively. These sites are necessary for maximal activation of mitogen-activated protein kinase (MAPK). Coexpression of catalytically inactive, but not wild-type, SHP-2 reduced LIFR- and gp130-mediated activation of MAPK up to 75%. Conversely, coexpression of the wild-type, but not catalytically inactive, SHP-1, a related phosphatase, reduced activity up to 80%, demonstrating that SHP-2 and SHP-1 have opposing effects on the MAPK pathway. Mutation of Y115 of the cytoplasmic domain of LIFR eliminates receptor-mediated tyrosine phosphorylation of SHP-2. In contrast, SHP-1 association with gp130 and LIFR is constitutive and independent of Y118 and Y115, respectively. SHP-1 has a positive regulatory role on LIF-stimulated vasoactive intestinal peptide (VIP) reporter gene expression in neuronal cells, whereas the effect of SHP-2 is negative. Furthermore, LIF-stimulated MAPK activation negatively regulates this VIP reporter gene induction. SHP-2 also negatively regulates LIF-dependent expression of choline acetyltransferase, but this regulation could be dissociated from its effects on MAPK activation. These data indicate that SHP-1 and SHP-2 are important regulators of LIF-dependent neuronal gene expression via both MAPK-dependent and -independent pathways.
Bartoe
J L
JL
Department of Pharmacology, University of Washington, Seattle 98195-7750, USA.
Nathanson
N M
NM
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D001665:Binding Sites; D019556:COS Cells; D002384:Catalysis; D002460:Cell Line; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D050822:Cytokine Receptor gp130; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects*; D006131:Growth Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053605:Leukemia Inhibitory Factor; D008156:Luciferases / Q000378:metabolism; D008222:Lymphokines / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D018121:Receptors, Cytokine / Q000502:physiology; D053606:Receptors, OSM-LIF; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
D015703:Antigens, CD; D006131:Growth Inhibitors; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008562:Membrane Glycoproteins; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050822:Cytokine Receptor gp130; D014660:Vasoactive Intestinal Peptide; D008156:Luciferases; D002795:Choline O-Acetyltransferase; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases