Burdon T, Stracey C, Chambers I, Nichols J, Smith A
Centre for Genome Research, University of Edinburgh, Kings Buildings, West Mains Road, Edinburgh, EH9 3JQ, Scotland.
Dev Biol. 1999 Jun 1;210(1):30-43. doi: 10.1006/dbio.1999.9265.
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 imply that the self-renewal signal from gp130 is a finely tuned balance of positive and negative effectors.
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。ES细胞中在gp130下游被激活的信号分子包括信号转导和转录激活因子3（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。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，该受体确实支持ES细胞的自我更新。事实上，形成干细胞集落所需的细胞因子浓度比未修饰的受体低100倍。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。在没有酪氨酸118的情况下信号传导失调的这些迹象通过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，证实了自我更新不需要ERK激活。事实上，在PD098059中培养可增强未分化ES细胞的生长。因此，ERK的激活似乎实际上会损害自我更新。这些数据表明，来自gp130的自我更新信号是正负效应器的精细平衡。
