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The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals

Oncogene volume 26, pages 2039–2047 (2007)Cite this article

Abstract

Phosphatidylinositol 3-kinase (PI3K) is necessary for thyroid stimulating hormone (TSH)-induced cell cycle progression. To determine the molecular mechanism linking PI3K to TSH, we have identified a serine residue in p85αPI3K phosphorylated by protein kinase A (PKA) in vitro and in vivo. Expression of an alanine mutant (p85A) abolished cyclic AMP/TSH-induced cell cycle progression and was lethal in thyroid cells (FRTL-5). The aspartic version of the p85αPI3K (p85D) inhibited apoptosis following TSH withdrawal. The p85αPI3K wild type not the p85A bound PKA regulatory subunit RIIβ in cells stimulated with cAMP or TSH. The binding of the aspartic version of p85αPI3K to RIIβ was independent of cAMP or TSH stimulation. Similarly, binding of PI3K to p21Ras and activation of AKT, a downstream PI3K target, were severely impaired in cells expressing the p85A mutant. Finally, we found that the catalytic activity of PI3K was stimulated by TSH in cells expressing the wild-type p85αPI3K but not in cells expressing p85A. This latter mutant did not affect the epidermal growth factor-stimulated PI3K activity. We suggest that (1) TSH–cAMP-induced PKA phosphorylates p85αPI3K at serine 83, (2) phosphorylated p85αPI3K binds RIIβ-PKA and targets PKAII to the membrane, and (3) PI3K activity and p21Ras binding to PI3K increase and activate PI3K downstream targets. This pathway is essential for the transmission of TSH–cAMP growth signals.

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Acknowledgements

We are indebted to Professor Angela Santoni for helpful suggestions and their continuous support. We are grateful to Professor Luisa Lenti at the Institute of Pathology of the University of Roma ‘La Sapienza’ for the help with the lipid kinase assay. This work was partly supported by MIUR (Italian Ministry of Education, University and Research). This paper is dedicated to the loving memory of Stelio Varrone.

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Authors and Affiliations

  1. Dipartimento di Patologia Molecolare IRCCS Neuromed, Località Camerelle, Pozzilli, Italy

    G De Gregorio, S Ucci, S Messina, A Di Pardo & A Porcellini

  2. Dipartimento di Medicina Sperimentale, Università ‘La Sapienza’, Viale Regina Elena, Roma, Italy

    A Coppa, A Nicolussi, S D'Inzeo & A Porcellini

  3. 1 Dipartimento di Biologia e Patologia Molecolare e Cellulare, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Università Federico II, Napoli, Italy

    C Cosentino & E V Avvedimento

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  1. G De Gregorio
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  2. A Coppa
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  3. C Cosentino
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  4. S Ucci
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Corresponding authors

Correspondence to E V Avvedimento or A Porcellini.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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De Gregorio, G., Coppa, A., Cosentino, C. et al. The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals. Oncogene 26, 2039–2047 (2007). https://doi.org/10.1038/sj.onc.1210011

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