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Obestatin stimulates Akt signalling in gastric cancer cells through beta-arrestin-mediated epidermal growth factor

Carlos J P Alvarez1, María Lodeiro, Marily Theodoropoulou

  • 1Laboratorio de Endocrinología Molecular y Celular, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), 15706 Santiago de Compostela, Spain.

Endocrine-Related Cancer
|January 21, 2009
PubMed

Insights

Obestatin activates Akt signaling through a novel pathway involving GPR39, beta-arrestin 1, and EGFR. This process requires specific phosphorylation events mediated by PDK1 and mTORC2, independent of G protein signaling.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Signaling

Background:

  • Obestatin, a gut peptide from the ghrelin gene, binds to the G protein-coupled receptor GPR39.
  • Understanding obestatin's intracellular signaling is crucial for elucidating its physiological roles.

Purpose of the Study:

  • To characterize the transmembrane signaling pathway of obestatin.
  • To identify the intracellular mechanisms responsible for Akt activation by obestatin.

Main Methods:

  • Sequential analysis of obestatin's transmembrane signaling pathway.
  • Investigated Akt activation through phosphorylation site analysis (T308, S473).
  • Examined the roles of G protein subunits, beta-arrestin 1, Src, and EGFR.

Main Results:

  • Akt activation requires T308 phosphorylation by phosphoinositide-dependent kinase 1 (PDK1) and S473 phosphorylation by mTOR kinase complex 2 (mTORC2).
  • Obestatin triggers GPR39/beta-arrestin 1/Src complex formation, leading to epidermal growth factor receptor (EGFR) transactivation.
  • Obestatin administration increased phosphorylation of mTOR and p70S6K1, paralleling Akt activation.

Conclusions:

  • A novel signaling pathway for obestatin-mediated Akt activation is proposed, involving beta-arrestin 1 scaffolding and EGFR transactivation.
  • This pathway is independent of G(i/o)-protein and Gbetagamma dimers.
  • Elucidates key molecular events in obestatin signaling.

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