PROTEIN KINASE-A ANTAGONIZES PLATELET-DERIVED GROWTH FACTOR-INDUCED SIGNALING BY MITOGEN-ACTIVATED PROTEIN-KINASE IN HUMAN ARTERIAL SMOOTH-MUSCLE CELLS
PROTEIN KINASE-A ANTAGONIZES PLATELET-DERIVED GROWTH FACTOR-INDUCED SIGNALING BY MITOGEN-ACTIVATED PROTEIN-KINASE IN HUMAN ARTERIAL SMOOTH-MUSCLE CELLS
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DOI：
10.1073/pnas.90.21.10300
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发表时间：
1993-11-01
影响因子：
11.1
通讯作者：
KREBS, EG
中科院分区：
文献类型：
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作者：
GRAVES, LM;BORNFELDT, KE;KREBS, EG
血小板衍生生长因子BB同源二聚体（PDGF-BB）刺激主动脉平滑肌细胞导致丝裂原活化蛋白激酶（MAPK）和MAPK激酶（MAPKK）的快速激活。发现增加cAMP和激活蛋白激酶A（PKA）的化合物-前列腺素E2、异丙肾上腺素、霍乱毒素和毛喉素-抑制PDGF-BB诱导的MAPKK和MAPK的激活。Forskolin，但不是无活性的类似物1，9-didoxyforskolin，抑制PDGF-BB刺激的MAPK和MAPK活化的剂量依赖性方式。在所有剂量的PDGF-BB或PDGF-AA下观察到MAPK信号传导的PKA拮抗作用。PKA在体外不抑制MAPKK和MAPK的活性，并且来自毛喉素处理的细胞提取物的MAPKK和MAPK可以分别被纯化的Raf-1和MAPKK正常激活，这表明PKA阻断了MAPKK上游的信号传导。无论是PDGF-BB刺激的PDGF受体β亚基的酪氨酸自磷酸化，也不是肌醇一磷酸的积累受到PKA活性增加的影响，这表明PKA抑制PDGF受体下游的事件。这项研究提供了一个例子，在平滑肌细胞的生理刺激激活的两个重要的信号系统之间的串扰，即PKA通路和生长因子激活的MAPK级联。
Stimulation of aortic smooth muscle cells with platelet-derived growth factor BB homodimer (PDGF-BB) leads to the rapid activation of mitogen-activated protein kinase (MAPK) and MAPK kinase (MAPKK). Compounds that increase cAMP and activate protein kinase A (PKA)-prostaglandin E2, isoproterenol, cholera toxin, and forskolin-were found to inhibit the PDGF-BB-induced activation of MAPKK and MAPK. Forskolin, but not the inactive analogue 1,9 -dideoxyforskolin, inhibited PDGF-BB-stimulated MAPKK and MAPK activation in a dose-dependent manner. PKA antagonism of MAPK signaling was observed at all doses of PDGF-BB or PDGF-AA. PKA did not inhibit MAPKK and MAPK activity in vitro, and MAPKK and MAPK from extracts of forskolin-treated cells could be activated normally with purified Raf-1 and MAPKK, respectively, suggesting that PKA blocked signaling upstream of MAPKK. Neither PDGF-BB-stimulated tyrosine autophosphorylation of the PDGF receptor beta subunit nor inositol monophosphate accumulation was affected by increased PKA activity, suggesting that PKA inhibits events downstream of the PDGF receptor. This study provides an example of cross talk between two important signaling systems activated by physiological stimuli in smooth muscle cells-namely, the PKA pathway and the growth factor-activated MAPK cascade.