Identification of p90RSK as the probable CREB-Ser133 kinase in human melanocytes.
Identification of p90RSK as the probable CREB-Ser133 kinase in human melanocytes.
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发表时间：
1995-03
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通讯作者：
M. Bohm;G. Moellmann;E. Cheng;M. Alvarez‐Franco;S. Wagner;P. Sassone-Corsi;R. Halaban
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作者：
M. Bohm;G. Moellmann;E. Cheng;M. Alvarez‐Franco;S. Wagner;P. Sassone-Corsi;R. Halaban
正常人黑素细胞只有在至少两种选择的肽生长因子的协同刺激下才能在体外增殖。在只有一种有丝分裂原存在的情况下，黑素细胞变得静止或死亡。这些有丝分裂原也增强了分化功能的表达，因为在它们的存在下，增殖的黑素细胞逐渐变得更加有色。为了评估参与这一双重反应的中间体，我们已经确定了几个已知的配体诱导的信号转导的激活状态。我们证明了肝细胞生长因子/分散因子、肥大/干细胞生长因子、碱性成纤维细胞生长因子和内皮素-1诱导cAMP反应元件结合蛋白的KID结构域中Ser133的磷酸化，这是该转录因子家族所有成员转录激活所必需的修饰，包括cAMP反应元件调节剂tau和激活转录因子1。协同生长因子的协同刺激延长了丝裂原活化蛋白激酶2级联的磷酸化状态和活性。协同生长因子对cAMP反应元件结合蛋白Ser133的磷酸化可能是由于p90RSK的激活，其次是p70S6K的激活。我们的发现支持这一概念，即起始于细胞表面的信号会聚到维持细胞分裂和分化的调节蛋白上。
Normal human melanocytes proliferate in vitro only in response to costimulation by at least two selected peptide growth factors. In the presence of only one mitogen, melanocytes become quiescent or die. These mitogens also enhance expression of differentiated functions, since in their presence the proliferating melanocytes become progressively more pigmented. To assess the intermediates participating in this dual response, we have determined the activated state of several known ligand-induced signal transducers. We demonstrate that hepatocyte growth factor/scatter factor, mast/stem-cell growth factor, basic fibroblast growth factor, and endothelin-1 induce phosphorylation of Ser133 within the KID domain of the cAMP-responsive element binding protein, a modification necessary for transcriptional activation of all members of this family of transcription factors, including also cAMP-responsive element modulator tau and activating transcription factor 1. The costimulation with synergistic growth factors prolonged the phosphorylated state and activity of the mitogen-activated protein kinase 2 cascade. cAMP-responsive element binding protein Ser133 phosphorylation in response to synergistic growth factors was due probably to the activation of p90RSK and, to a lesser extent, to p70S6K. Our findings support the concept that signals initiated at the cell surface converge on regulatory proteins that sustain both cell division and differentiation.