DUAL AND OPPOSING ROLES OF SHP 2 IN CNTF SIGNALING

描述src同源2（SH 2）结构域蛋白酪氨酸 磷酸酶SHP-2被认为是一种重要的正调节因子， 几种促有丝分裂信号通路。 SHP-2最近被证明 被酪氨酸磷酸化并被募集到细胞的gp 130/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不具有对应答性细胞的增殖作用。 细胞，而是增强交感神经的存活和分化， 运动和感觉神经元。 在初步研究部分， 申请人证明了干扰性SH 2结构域突变体的表达 SHP-2在神经母细胞瘤细胞系中的表达增加了CNTF对神经母细胞瘤细胞的诱导， 血管活性肠肽（VIP）报告基因，并在培养 交感神经元导致内源性VIP、物质 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 消除了CNTF对c-Fos蛋白水平的诱导。 国家工作队成员 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， STAT是诱导VIP基因所必需的。 综合来看，这些数据 表明SHP-2在信号级联中具有双重和相反作用 由相同的配体触发，如其在 VIP、SP和ChAT水平的诱导以及在诱导 c-Fos水平。 在这份提案中，他们将详细研究 由CNTF等神经细胞因子激活， SHP-2如何调节这些平行信号通路的机制。

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.