cAMP signaling selectively influences Ras effectors pathways

被引:83
作者
Ciullo, I
Diez-Roux, G
Di Domenico, M
Migliaccio, A
Avvedimento, EV
机构
[1] Univ Naples Federico II, Fac Med,Policlin 2, Dipartimento Biol & Patol Mol & Cellulare, CNR, I-80131 Naples, Italy
[2] Univ Catanzaro, Fac Med, Dipartimento Med Sperimentale & Clin, I-88100 Catanzaro, Italy
[3] Univ Naples 2, Ist Patol Gen, I-80138 Naples, Italy
关键词
transduction; cAMP-dependent kinase; Ras and GTP binding proteins; PI3-kinases; growth; thyroid differentiation;
D O I
10.1038/sj.onc.1204219
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1186 / 1192
页数:7
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