DUAL AND OPPOSING ROLES OF SHP 2 IN CNTF SIGNALING

SHP 2 在 CNTF 信号传导中的双重和对立角色

• 批准号: 2692718
• 负责人: STEVEN A REEVES
• 金额: $ 19.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-24 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2692718
• 关键词: Animalia; acetylcholine; animal genetic material tag; biological signal transduction; cell differentiation; cell proliferation; developmental genetics; developmental neurobiology; enzyme activity; gene induction /repression; neurogenesis; neurogenetics; neurons; neurotransmitter biosynthesis; neurotrophic factors; protein tyrosine phosphatase; sympathetic nervous system; tissue /cell culture

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.

描述 含有 src 同源 2 (SH2) 结构域的蛋白质酪氨酸 磷酸酶 SHP-2 被认为是重要的正调节因子 几种有丝分裂信号通路。 SHP-2 最近被证明可以 被酪氨酸磷酸化并募集至 gp130/LIFR 亚基 睫状神经营养因子刺激后的 CNTF 受体复合物 （CNTF）。 然而，CNTF 对响应性不具有增殖作用。 细胞，而是增强交感神经的存活和分化， 运动神经元和感觉神经元。 在初步研究部分 申请人证明了干扰SH2结构域突变体的表达 神经母细胞瘤细胞系中的 SHP-2 会增加 CNTF 的诱导 血管活性肠肽（VIP）报告基因和培养物 交感神经元导致内源性 VIP、物质的上调 P (SP) 和胆碱乙酰转移酶 (ChAT) 基因表达。 他们还 在平行研究中发现 SHP-2 干扰突变体的表达 消除 CNTF 对 c-Fos 蛋白水平的诱导。 CNTF成员 细胞因子家族通过激活信号通路传递信号 涉及 STAT 和 Fos-Jun (AP-1) 转录因子并激活 STAT 对于 VIP 基因的诱导是必需的。 综合起来，这些数据 表明 SHP-2 在信号级联中具有双重且相反的作用 由相同配体触发，如其负功能所示 VIP、SP 和 ChAT 水平的诱导以及诱导中的积极功能 c-Fos 水平。 在此提案中，他们将详细研究途径 由 CNTF 等神经细胞因子激活并定义分子 SHP-2 如何调节这些平行信号通路的机制。