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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0192v1 16/2/599    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Alvarez, C. Articles by Pazos, Y. Search for Related Content PubMed PubMed Citation Articles by Alvarez, C. Articles by Pazos, Y.

C Alvarez, Laboratorio de Endocrinologia Molecular y Celular. Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
M Lodeiro, Laboratorio de Endocrinologia Molecular y Celular. Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
M Theodoropoulou, Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany
J Camina, Laboratorio de Endocrinologia Molecular y Celular. Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
F Casanueva, Laboratorio de Endocrinologia Molecular y Celular. Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
Y Pazos, Laboratorio de Endocrinologia Molecular y Celular. Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain

Correspondence: Yolanda Pazos, Email: yolanda.pazos{at}usc.es

Abstract

Obestatin was identified as a gut peptide encoded by the ghrelin gene that interacts with the G protein-coupled receptor, GPR39. In this work, a sequential analysis of its transmembrane signalling pathway has been undertaken to characterize the intracellular mechanisms responsible for Akt activation. The results show that Akt activation requires the phosphorylation of T308 in the A-loop by the phosphoinositide-dependent kinase 1 (PDK1) and S473 within the HM by the mammalian target of rapamycin (mTOR) kinase complex 2 (mTORC2: Rictor, mLST8, mSin1, mTOR kinase) with participation neither of Gi/o-protein nor Gβ dimers. Obestatin induces the association of GPR39/β-arrestin 1/Src signalling complex resulting in the transactivation of the epidermal growth factor receptor (EGFR) and downstream Akt signalling. Upon administration of obestatin, phosphorylation of mTOR (S2448) and p70S6K1 (T389) rise with a time course that parallels that of Akt activation. Based on the experimental data obtained, a signalling pathway involving a β-arrestin 1 scaffolding complex and EGFR to activate Akt signalling is proposed.