Muscarinic M3 and epidermal growth factor receptors activate mutually inhibitory signaling cascades in human neuroblastoma SH-SY5Y cells.
Regulatory interactions among individual receptor-coupled signal transduction systems are critically important for establishing cellular responses in the face of multiple stimuli. In this study, potential regulatory interactions between signal transduction systems activated by growth factor receptors and by G-protein-coupled receptors were examined using human neuroblastoma SH-SY5Y cells which express endogenous epidermal growth factor (EGF) and muscarinic M3 receptors. Activation of muscarinic receptors with carbachol was found to inhibit EGF-induced signaling, including tyrosine phosphorylation of the adaptor protein Cbl and of the EGF receptor, and complex formation between Shc proteins and the EGF receptor and Grb2. Protein kinase C, which is activated by muscarinic M3 receptors, mediated this inhibitory cross-talk. Activation of EGF receptors was found to inhibit muscarinic receptor-induced tyrosine phosphorylation of focal adhesion kinase and paxillin. Reactive oxygen species, which are formed as components of the EGF signaling cascade, mediated this inhibitory cross-talk. These mutual inhibitory interactions demonstrate novel mechanisms for neuronal integration of multiple signals generated by activation of receptors by neurotransmitters and growth factors.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, 35294-0017, USA.
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D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002217:Carbachol / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051380:GRB2 Adaptor Protein; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism*; D050722:Oncogene Protein v-cbl; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015815:Cell Adhesion Molecules; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D050722:Oncogene Protein v-cbl; D011506:Proteins; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D015682:Retroviridae Proteins, Oncogenic; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D002217:Carbachol; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D013755:Tetradecanoylphorbol Acetate