Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells
Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells
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DOI：
10.1006/dbio.1999.9265
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发表时间：
1999-06-01
影响因子：
2.7
通讯作者：
Smith, A
中科院分区：
文献类型：
--
作者：
Burdon, T;Stracey, C;Smith, A
多能性小鼠胚胎干细胞（ES细胞）的增殖依赖于通过细胞因子受体亚基gp130转导的信号。在ES细胞中，gp130下游激活的信号分子包括STAT3、蛋白酪氨酸磷酸酶SHP - 2以及丝裂原活化蛋白激酶ERK1和ERK2。一种在gp130胞质结构域中酪氨酸118发生突变的嵌合受体不能结合SHP - 2，也无法激活ERK。然而，这种受体确实支持ES细胞的自我更新。事实上，与未修饰的受体相比，它在细胞因子浓度低100倍的情况下就能形成干细胞集落。此外，在高细胞因子浓度下观察到ES细胞形态和生长发生改变。在缺乏酪氨酸118的情况下，这些信号失调的迹象通过STAT3的持续激活得到证实。通过在MEK抑制剂PD098059存在的情况下培养多能性ES细胞，证实了ERK激活对于自我更新不是必需的。事实上，在PD098059中培养未分化的ES细胞，其生长得到增强。因此，ERK的激活似乎会积极地损害自我更新。这些数据表明，来自gp130的自我更新信号是正负效应因子的精细平衡。（C）1999学术出版社
The propagation of pluripotent mouse embryonic stem (ES) cells depends on signals transduced through, the cytokine receptor subunit gp130. Signalling molecules activated downstream of gp130 in ES cells include STAT3, the protein tyrosine phosphatase SHP-2 and the mitogen-activated protein kinases, ERK1 and ERK2. A chimaeric receptor in which tyrosine 118 in the gp130 cytoplasmic domain was mutated did not engage SHP-2 and failed to activate ERKs. However, this receptor did support ES cell self-renewal. In fact, stem cell colonies formed at 100-fold lower concentrations of cytokine than the unmodified receptor. Moreover, altered ES cell morphology and growth were observed at high cytokine concentrations. These indications of deregulated signalling in the absence of tyrosine 118 were substantiated by sustained activation of STAT3. Confirmation that ERK activation is not required for self-renewal was obtained by propagation of pluripotent ES cells in the presence of the MEK inhibitor PD098059. In fact, the growth of undifferentiated ES cells was enhanced by culture in PD098059. Thus activation of ERKs appears actively to impair self-renewal. These data that the self-renewal signal from gp130 is a finely tuned balance of positive and negative effecters. (C) 1999 Academic Press.