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Endocrine-Related Cancer 16 (2) 599 -611     DOI: 10.1677/ERC-08-0192
Copyright © 2009 by the Society for Endocrinology
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Obestatin stimulates Akt signalling in gastric cancer cells through β-arrestin-mediated epidermal growth factor receptor transactivation

 Carlos J P Álvarez1,2, María Lodeiro1,2, Marily Theodoropoulou1,3, Jesús P Camiña1,2, Felipe F Casanueva1,2,4 and Yolanda Pazos1,2

1 Laboratorio de Endocrinología Molecular y Celular, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), A Choupana, s/n., 15706 Santiago de Compostela, Spain
2 CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain
3 Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany
4 Departamento de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, Spain

(Correspondence should be addressed to Y Pazos; Email: yolanda.pazos{at}usc.es)

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{gamma} 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.






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