Rahmatullah M, Schroering A, Rothblum K, Stahl R C, Urban B, Carey D J
Henry Hood Research Program, Weis Center for Research, Penn State College of Medicine, Danville, Pennsylvania 17822-2613, USA.
Mol Cell Biol. 1998 Nov;18(11):6245-52. doi: 10.1128/MCB.18.11.6245.
A peptide corresponding to the epidermal growth factor homology domain of beta-heregulin stimulated autophosphorylation of the heregulin receptors erbB2 and erbB3 in Schwann cells and activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2. Heregulin-dependent activation of PAK65, a component of the stress-activated signaling pathway, ribosomal S6 kinase, and a cyclic AMP (cAMP) response element binding protein (CREB) kinase, identified as p95(RSK2), was also observed. Receptor phosphorylation and activation of these kinases in response to heregulin occurred in the absence of forskolin stimulation and were not augmented in cells treated with forskolin, a direct activator of adenylyl cyclase. Schwann cell proliferation in response to heregulin was observed only when the cells were also exposed to an agent that elevates cAMP levels. In the absence of heregulin, elevation of cAMP levels failed to stimulate Schwann cell proliferation. Forskolin significantly enhanced heregulin-stimulated expression of cyclin D and phosphorylation of the retinoblastoma gene product. In cells treated with both heregulin and forskolin there was a sustained accumulation of phospho-CREB, which was not observed in cells treated with either agent alone. Heregulin and forskolin synergistically activated transcription of a cyclin D promoter construct. These results demonstrate that heregulin-stimulated activation of MAP kinase is not sufficient to induce maximal Schwann cell proliferation. Expression of critical cell cycle regulatory proteins and cell division require activation of both heregulin and cAMP-dependent processes.
一种与β-神经调节蛋白的表皮生长因子同源结构域相对应的肽，可刺激雪旺细胞中神经调节蛋白受体erbB2和erbB3的自磷酸化，并激活丝裂原活化蛋白（MAP）激酶ERK1和ERK2。还观察到了应激激活信号通路的一个组成部分PAK65、核糖体S6激酶以及被鉴定为p95（RSK2）的环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）激酶的神经调节蛋白依赖性激活。在不存在福斯可林刺激的情况下，神经调节蛋白可引起这些激酶的受体磷酸化和激活，且在用腺苷酸环化酶的直接激活剂福斯可林处理的细胞中并未增强。仅当细胞同时暴露于一种可提高cAMP水平的试剂时，才观察到雪旺细胞对神经调节蛋白的增殖反应。在不存在神经调节蛋白的情况下，cAMP水平的升高未能刺激雪旺细胞增殖。福斯可林显著增强了神经调节蛋白刺激的细胞周期蛋白D的表达以及视网膜母细胞瘤基因产物的磷酸化。在用神经调节蛋白和福斯可林共同处理的细胞中，磷酸化CREB持续积累，而单独用任何一种试剂处理的细胞中均未观察到这种现象。神经调节蛋白和福斯可林协同激活细胞周期蛋白D启动子构建体的转录。这些结果表明，神经调节蛋白刺激的MAP激酶激活不足以诱导雪旺细胞的最大增殖。关键细胞周期调节蛋白的表达和细胞分裂需要神经调节蛋白和cAMP依赖性过程的共同激活。
