c-Src regulates Akt signaling in response to ghrelin via beta-arrestin signaling-independent and -dependent mechanisms.
The aim of the present study was to identify the signaling mechanisms to ghrelin-stimulated activation of the serine/threonine kinase Akt. In human embryonic kidney 293 (HEK293) cells transfected with GHS-R1a, ghrelin leads to the activation of Akt through the interplay of distinct signaling mechanisms: an early G(i/o) protein-dependent pathway and a late pathway mediated by beta-arrestins. The starting point is the G(i/o)-protein dependent PI3K activation that leads to the membrane recruitment of Akt, which is phosphorylated at Y by c-Src with the subsequent phosphorylation at A-loop (T308) and HM (S473) by PDK1 and mTORC2, respectively. Once the receptor is activated, a second signaling pathway is mediated by beta-arrestins 1 and 2, involving the recruitment of at least beta-arrestins, c-Src and Akt. This beta-arrestin-scaffolded complex leads to full activation of Akt through PDK1 and mTORC2, which are not associated to the complex. In agreement with these results, assays performed in 3T3-L1 preadipocyte cells indicate that beta-arrestins and c-Src are implicated in the activation of Akt in response to ghrelin through the GHS-R1a. In summary this work reveals that c-Src is crucially involved in the ghrelin-mediated Akt activation. Furthermore, the results support the view that beta-arrestins act as both scaffolding proteins and signal transducers on Akt activation.
Lodeiro
Maria
M
Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigaciones Sanitarias, Complejo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela, Spain.
Theodoropoulou
Marily
M
Pardo
Maria
M
Casanueva
Felipe F
FF
Camiña
Jesus P
JP
D041721:3T3-L1 Cells; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D054439:Ghrelin / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054440:Receptors, Ghrelin / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins; D019061:src-Family Kinases
D019390:Arrestins; D054439:Ghrelin; D011518:Proto-Oncogene Proteins; D054440:Receptors, Ghrelin; D000071557:beta-Arrestins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051057:Proto-Oncogene Proteins c-akt; D019206:GTP-Binding Protein alpha Subunits, Gi-Go