cAMP signaling selectively influences Ras effectors pathways
cAMP signaling selectively influences Ras effectors pathways
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DOI：
10.1038/sj.onc.1204219
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发表时间：
2001-03-08
期刊：
影响因子：
8
通讯作者：
Avvedimento, EV
中科院分区：
文献类型：
--
作者：
Ciullo, I;Diez-Roux, G;Avvedimento, EV
促甲状腺激素(TSH)通过七个跨膜G蛋白偶联受体刺激甲状腺细胞的存活和生长。TSH上调细胞内环磷酸腺苷(CAMP)水平，激活蛋白激酶A(PKA)，最近的证据表明p21RAS是TSH诱导有丝分裂所必需的，但其分子机制(S)尚不清楚。在TSH诱导的细胞周期中，Ras p21活性是GO-G1转换所必需的，Ras对TSH信号转导的下游效应是P85-p110 PI3K。我们发现，PI3K抑制剂阻断TSH诱导的DNA合成，cAMP-PKA刺激PI3K-p21 Ras复合体的形成，并减少甲状腺和其他类型细胞中Ras-Raf1复合体的形成。此外，PKA使免疫沉淀的P85磷酸化，细胞提取物的PKA磷酸化显著刺激PI3K-RAS复合体的形成，我们认为PKA磷酸化P85并稳定复合体p110-P85，增强PI3K和p21RAS的相互作用，同时，cAMP通过减少Raf1对RAS的可获得性而抑制Raf-1-ERK信号转导，在这种情况下，PI3K信号是有利的。这些结果表明，在cAMP诱导的细胞增殖中，PI3K是RAS效应的重要介导者，并阐明了cAMP如何选择性地影响RAS效应通路。
Thyrotropin (TSH) stimulates survival and growth of thyroid cells via a seven transmembrane G protein-coupled receptor. TSH elevates the intracellular cyclic AMP (cAMP) levels activating protein kinase A (PKA), Recent evidence indicates that p21 Ras is required for TSH-induced mitogenesis, but the molecular mechanism(s) is not known. Here we report that Ras p21 activity is necessary for the Go- G1 transition in TSH induced cycle and that the downstream effector of Ras upon TSH signaling is p85-p110 PI3K, We show that PI3K inhibitors block TSH-induced DNA synthesis, cAMP-PKA stimulate the formation of the complex PI3K-p21 Ras and reduce the complex Ras-Raf1 in thyroid and other cells types. Moreover, PKA phosphorylates immunoprecipitated p85 and PKA phosphorylation of cell extracts significantly stimulates the formation of the complex PI3K-Ras, We suggest that PKA phosphorylates p85 and stabilizes the complex p110-p85, enhancing the interaction PI3K and p21 Ras, Simultaneously, cAMP inhibits Raf-1-ERK signaling by decreasing Raf1 availability to Ras, Under these circumstances PI3K signaling is favored. These results indicate that PI3K is an important mediator of Ras effects in cAMP-induced proliferation and illustrates how cAMP can selectively influence Ras effector pathways.