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: 6147902
• 负责人: STEVEN A REEVES
• 金额: $ 5万
• 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/6147902
• 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SRC同源性2（SH2）含域的蛋白酪氨酸 磷酸酶SHP-2已被认为是 几种有丝分裂信号通路。 SHP-2最近被证明 被酪氨酸磷酸化并招募到GP130/LIFR亚基 用睫状神经营养因子刺激后CNTF受体复合物复合物 （CNTF）。 但是，CNTF对响应迅速效果没有​​增生 细胞，而是增强了交感神经的生存和分化， 运动和感觉神经元。 在“初步研究”部分 申请人证明了干扰SH2域突变体的表达 神经母细胞瘤细胞系中的SHP-2增加了A的CNTF诱导 血管活性肠肽（VIP）报告基因和在培养物中 交感神经元导致内源性VIP的上调 P（SP）和胆碱乙酰转移酶（CHAT）基因表达。 他们也是 在平行研究中发现SHP-2干扰突变体的表达 废除CNTF诱导C-FOS蛋白水平。 CNTF的成员 细胞因子家族通过激活信号通路传输信号 涉及Stat和Fos-Jun（AP-1）转录因子并激活 STAT对于诱导VIP基因是必需的。 综上所述，这些数据 表明SHP-2在信号级联中具有双重和相反的角色 由同一配体触发，如其负面功能所示 诱导VIP，SP和聊天水平以及诱导的正功能 C-FOS水平。 在此提案中，他们将详细检查道路 由CNTF等神经细胞动力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。