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  • Original Paper
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cAMP signaling selectively influences Ras effectors pathways

Oncogene volume 20, pages 1186–1192 (2001)Cite this article

Abstract

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.

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Acknowledgements

This work was supported by grants from ‘Associazione Italiana per la Ricerca sul Cancro (AIRC)’; Targeted Project Biotechnology CNR; and MURST (Italian Department of University and Research). G Diez-Roux is a recipient of an EMBO long term fellowship.

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Author notes

  1. Ilaria Ciullo and Graciana Diez-Roux: I Ciullo and G Diez-Roux contributed equally to this work

Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Molecolare e Cellulare, Centro di Endocrinologia ed Oncologia Sperimentale del C.N.R., Facoltà di Medicina, Università “Federico II” via S.Pansini 5, Napoli, Italy

    Ilaria Ciullo, Graciana Diez-Roux & Enrico V Avvedimento

  2. Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina, Università di Catanzaro, via T. Campanella 5, Catanzaro, 88100, Italy

    Enrico V Avvedimento

  3. Istituto di Patologia Generale, II Università di Napoli, Largo S. Aniello a Caponapoli, Napoli, 2-80138, Italy

    Marina Di Domenico & Antimo Migliaccio

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  1. Ilaria Ciullo
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  2. Graciana Diez-Roux
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  4. Antimo Migliaccio
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Ciullo, I., Diez-Roux, G., Di Domenico, M. et al. cAMP signaling selectively influences Ras effectors pathways. Oncogene 20, 1186–1192 (2001). https://doi.org/10.1038/sj.onc.1204219

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  • DOI: https://doi.org/10.1038/sj.onc.1204219

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