Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2
Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2
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DOI：
10.1074/jbc.273.11.6233
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发表时间：
1998-03-13
影响因子：
4.8
通讯作者：
Reeves, SA
中科院分区：
文献类型：
--
作者：
Servidei, T;Aoki, Y;Reeves, SA
含有 src 同源 2 (SH2) 结构域的蛋白酪氨酸磷酸酶 SHP-2 被认为是多种有丝分裂信号通路的重要正调节因子。最近，SHP-2 被证明可被酪氨酸磷酸化，并在 CNTF 刺激后被募集至睫状神经营养因子 (CNTF) 受体复合物的 gp130 成分。然而，CNTF 对反应性细胞没有增殖作用，而是增强交感神经元、运动神经元和感觉神经元的存活和分化。在这项研究中，神经母细胞瘤细胞系 NBFL 中 SHP-2 干扰突变体的表达增加了 CNTF 对血管活性肠肽 (VIP) 报告基因的诱导，并且在交感神经元培养物中，导致内源性 VIP 和 P 物质 (SP) 基因表达上调。 CNTF 细胞因子家族的成员通过激活涉及 STAT 和 Fos-Jun 转录因子的信号通路来传递信号。在 CNTF 刺激的 NBFL 细胞中，组成型表达 SHP-2 干扰突变体，STAT/DNA 复合物的形成增加并延长，但 AP-1 结合活性降低，这反映了 mRNA 和蛋白质水平上 c-fos 表达的下调。总而言之，这些数据表明 SHP-2 在由同一配体触发的信号级联中具有双重且相反的作用，如其差异调节 STAT 和 AP-1 转录因子活性水平的能力所示。
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 component of the ciliary neurotrophic factor (CNTF) receptor complex upon stimulation with 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 this study, expression of an interfering mutant of SHP-2 in the neuroblastoma cell line NBFL increased CNTF induction of a vasoactive intestinal peptide (VIP) reporter gene, and in cultures of sympathetic neurons, it resulted in an up-regulation of endogenous VIP and substance P (SP) gene expression. Members of the CNTF family of cytokines transmit their signal by activating signaling pathways involving both STAT and Fos-Jun transcription factors. In CNTF-stimulated NBFL cells that constitutively express the SHP-2 interfering mutant, there was increased and prolonged formation of STAT/DNA complexes, but decreased AP-1 binding activity, that mirrored a down-regulation of c-fos expression both at the mRNA and protein level. 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 ability to differentially regulate the levels of activity of both STAT and AP-1 transcription factors.