Differential regulation of extracellular signal-regulated protein kinase 1 and Jun N-terminal kinase 1 by Ca2+ and protein kinase C in endothelin-stimulated Rat-1 cells.
Differential regulation of extracellular signal-regulated protein kinase 1 and Jun N-terminal kinase 1 by Ca2+ and protein kinase C in endothelin-stimulated Rat-1 cells.
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内皮素刺激的 Rat-1 细胞中 Ca2 和蛋白激酶 C 对细胞外信号调节蛋白激酶 1 和 Jun N 末端激酶 1 的差异调节。
作者：
K. Cadwallader;J. Beltman;F. McCormick;S. Cook
细胞外信号调节蛋白激酶（ERK）和Jun N-末端激酶（JNK）信号级联将信号从细胞质传递到细胞核，在那里它们调节基因表达。比较了溶血磷脂酸（LPA）和内皮素1（Et-1）对Rat-1细胞ERK 1的激活作用。两者刺激DNA合成的程度相似，但与LPA相反，Et-1没有刺激持续的ERK 1激活，这是一个被认为对成纤维细胞增殖很重要的信号。Et-1，而不是LPA，能够激活JNK 1;药理学分析表明，相同的EtA受体介导DNA合成，ERK 1和JNK 1激活。然而，JNK 1的激活需要比刺激ERK 1或DNA合成所需的更高浓度的Et-1。ERK 1和JNK 1的信号转导部分受到百日咳毒素的抑制，这表明这两种途径部分受到Gi或G 0蛋白的调节。Et-1对JNK 1的激活滞后于ERK 1的激活，但不依赖于ERK 1，因为PD 98059是一种丝裂原活化蛋白激酶（或ERK）激酶的抑制剂，对JNK 1的激活没有影响。与最近的研究相反，激活蛋白激酶C（PKC）或Ca 2+流量抑制JNK 1的激活，但不ERK 1;此外，抑制PKC或螯合的Ca 2+增强JNK 1激活Et-1，但不是茴香霉素，并再次对ERK 1的激活几乎没有影响。这些结果表明，相同的G蛋白偶联受体可以激活ERK和JNK信号通路，但这两个激酶级联似乎是独立的，平行的途径，由PKC和Ca 2+的差异调节。结果进行了讨论的ERK和JNK在增殖信号的作用。
The extracellular signal-regulated protein kinase (ERK) and Jun N-terminal kinase (JNK) signalling cascades transduce signals from the cell cytoplasm to the nucleus, where they regulate gene expression. The activation of ERK1 by lysophosphatidic acid (LPA) and endothelin 1 (Et-1) was compared in Rat-1 cells. Both stimulated DNA synthesis to a similar degree but, in contrast with LPA, Et-1 did not stimulate sustained ERK1 activation, a signal that is thought to be important for the proliferation of fibroblasts. Et-1, but not LPA, was able to activate JNK1; pharmacological analysis revealed that the same EtA receptor mediates DNA synthesis, ERK1 and JNK1 activation. However, activation of JNK1 required higher concentrations of Et-1 than was required for stimulation of ERK1 or DNA synthesis. Signalling to ERK1 and JNK1 was partly inhibited by pertussis toxin, suggesting that both pathways are regulated in part by Gi or G0 proteins. Activation of JNK1 by Et-1 lagged behind ERK1 activation but was not dependent on it because PD98059, an inhibitor of mitogen-activated protein kinase (or ERK) kinase, was without effect on JNK1 activation. In contrast with recent studies, activation of protein kinase C (PKC) or Ca2+ fluxes inhibited activation of JNK1 but not ERK1; furthermore inhibition of PKC or sequestration of Ca2+ potentiated JNK1 activation by Et-1 but not by anisomycin, and again had little effect on ERK1 activation. These results demonstrate that the same G-protein-coupled receptor can activate both the ERK and JNK signal pathways but the two kinase cascades seem to be separate, parallel pathways that are differentially regulated by PKC and Ca2+. The results are discussed in terms of the role of ERK and JNK in proliferative signalling.