Zhang L, Jope R S
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, 35294-0017, USA.
Biochem Biophys Res Commun. 1999 Feb 24;255(3):774-7. doi: 10.1006/bbrc.1999.0273.
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.
在面对多种刺激时，各个受体偶联信号转导系统之间的调节相互作用对于建立细胞反应至关重要。在本研究中，利用表达内源性表皮生长因子（EGF）和毒蕈碱型M3受体的人神经母细胞瘤SH-SY5Y细胞，研究了生长因子受体和G蛋白偶联受体激活的信号转导系统之间潜在的调节相互作用。发现用卡巴胆碱激活毒蕈碱受体可抑制EGF诱导的信号传导，包括衔接蛋白Cbl和EGF受体的酪氨酸磷酸化，以及Shc蛋白与EGF受体和Grb2之间的复合物形成。由毒蕈碱型M3受体激活的蛋白激酶C介导了这种抑制性串扰。发现EGF受体的激活可抑制毒蕈碱受体诱导的粘着斑激酶和桩蛋白的酪氨酸磷酸化。作为EGF信号级联反应组成部分而形成的活性氧介导了这种抑制性串扰。这些相互抑制性相互作用展示了神经递质和生长因子激活受体所产生的多种信号进行神经元整合的新机制。
