Obestatin stimulates Akt signalling in gastric cancer cells through beta-arrestin-mediated epidermal growth factor receptor transactivation.
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 G(i)(/o)-protein nor Gbetagamma dimers. Obestatin induces the association of GPR39/beta-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 beta-arrestin 1 scaffolding complex and EGFR to activate Akt signalling is proposed.
Alvarez
Carlos J P
CJ
Laboratorio de Endocrinología Molecular y Celular, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), 15706 Santiago de Compostela, Spain.
Lodeiro
María
M
Theodoropoulou
Marily
M
Camiña
Jesús P
JP
Casanueva
Felipe F
FF
Pazos
Yolanda
Y
D019390:Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D054439:Ghrelin; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D036361:Peptide Hormones / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D019390:Arrestins; D054439:Ghrelin; D036361:Peptide Hormones; D034741:RNA, Small Interfering; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C505799:obestatin, human; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt