A role for the SHP-2 tyrosine phosphatase in nerve growth factor-induced PC12 cell differentiation
A role for the SHP-2 tyrosine phosphatase in nerve growth factor-induced PC12 cell differentiation
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DOI：
10.1091/mbc.8.8.1575
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发表时间：
1997-08-01
影响因子：
3.3
通讯作者：
Krebs, EG
中科院分区：
文献类型：
--
作者：
Wright, JH;Drueckes, P;Krebs, EG
SHP-1和SHP-2是含有两个相邻src同源2结构域的细胞内蛋白酪氨酸磷酸酶，其将这些磷酸酶靶向细胞表面受体信号传导复合物并在受体信号转导中起作用。本研究以PC 12细胞为研究对象，探讨SHP-1和SHP-2在神经生长因子（NGF）诱导神经元分化中的作用。通过使用神经突生长作为分化的标志物，评估了SHP-1和SHP-2的转染构建体的效果。过表达无催化活性的SHP-2，而不是无催化活性的SHP-1，阻断了NGF刺激的神经突生长。丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路对PC 12细胞的形态分化具有重要作用，SHP-1和SHP-2在其他受体信号通路中均位于MAPK的上游。通过引入SHP-2磷酸酶突变体沿着血凝素标记的MAPK，证明了SHP-2而不是SHP-1在NGF激活MAPK中的积极作用。SHP-2突变体沿着MAPK激酶突变形式的共表达研究表明，SHP-2在MAPK激酶上游发挥作用，MAPK在NGF诱导的神经突生长中发挥作用。
SHP-1 and SHP-2 are intracellular protein tyrosine phosphatases containing two adjacent src homology 2 domains that target these phosphatases to cell surface receptor signaling complexes and play a role in receptor signal transduction. In this report the PC12 cell system was used to investigate the potential roles of SHP-1 and SHP-2 in the induction of neuronal differentiation by nerve growth factor (NGF). By using neurite outgrowth as a marker for differentiation, the effects of transfected constructs of SHP-1 and SHP-2 were assessed. Overexpression of a catalytically inactive SHP-2, but not a catalytically inactive SHP-1, blocked NGF-stimulated neurite outgrowth. The mitogen-activated protein kinase (MAPK) signaling cascade is important for the morphological differentiation in PC12 cells, and both SHP-1 and SHP-2 have been implicated to act upstream of MAPK in other receptor signaling systems. A positive role for SHP-2 but not SHP-1 in the activation of MAPK by NGF was demonstrated by introduction of the SHP-2 phosphatase mutants along with hemagglutinin-tagged MAPK. Coexpression studies with the SHP-2 mutant along with mutant forms of MAPK kinase suggested that SHP-2 functions upstream of MAPK kinase and MAPK in NGF-induced neurite outgrowth.