INHIBITION OF THE EGF-ACTIVATED MAP KINASE SIGNALING PATHWAY BY ADENOSINE-3',5'-MONOPHOSPHATE
INHIBITION OF THE EGF-ACTIVATED MAP KINASE SIGNALING PATHWAY BY ADENOSINE-3',5'-MONOPHOSPHATE
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DOI：
10.1126/science.7694366
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发表时间：
1993-11-12
期刊：
影响因子：
56.9
通讯作者：
STURGILL, TW
中科院分区：
文献类型：
--
作者：
WU, J;DENT, P;STURGILL, TW
丝裂原激活蛋白 (MAP) 激酶 P42mapk 和 p44mapk 在表皮生长因子 (EGF) 和其他药物刺激的细胞中被激活。 EGF 激活 MAP 激酶 (MAPK) 的主要途径包括依次激活鸟嘌呤核苷酸交换因子 Sos、三磷酸鸟苷结合蛋白 Ras 以及蛋白激酶 Raf-1、MAPK 激酶 (MKK) 和 MAPK。由于 3',5'-单磷酸腺苷 (cAMP) 不会激活 MAPK 并具有一些相反的生理作用，因此研究了用毛喉素和 3-异丁基-1-甲基黄嘌呤增加细胞内 cAMP 浓度对 EGF 刺激的 MAPK 途径的影响。 cAMP 浓度的增加可阻断 Rat1hER 成纤维细胞中 Raf-1、MKK 和 MAPK 的激活，同时调节域中丝氨酸 43 上的 Raf-1 磷酸化增加三倍。 Raf-1 在体外和体内的磷酸化会降低其与 Ras 结合的表观亲和力，并可能有助于 cAMP 的阻断。
Mitogen-activated protein (MAP) kinases P42mapk and p44mapk are activated in cells stimulated with epidermal growth factor (EGF) and other agents. A principal pathway for MAP kinase (MAPK) activation by EGF consists of sequential activations of the guanine nucleotide exchange factor Sos, the guanosine triphosphate binding protein Ras, and the protein kinases Raf-1, MAPK kinase (MKK), and MAPK. Because adenosine 3',5'-monophosphate (cAMP) does not activate MAPK and has some opposing physiologic effects, the effect of increasing intracellular concentrations of cAMP with forskolin and 3-isobutyl-1-methylxanthine on the EGF-stimulated MAPK pathway was studied. Increased concentrations of cAMP blocked activation of Raf-1, MKK, and MAPK in Rat1hER fibroblasts, accompanied by a threefold increase in Raf-1 phosphorylation on serine 43 in the regulatory domain. Phosphorylation of Raf-1 in vitro and in vivo reduces the apparent affinity with which it binds to Ras and may contribute to the blockade by cAMP.