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.
Mesh Terms:
3T3-L1 Cells, Animals, Arrestins, Cell Line, Enzyme Activation, GTP-Binding Protein alpha Subunits, Gi-Go, Ghrelin, Humans, Mice, Phosphorylation, Protein Transport, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Receptors, Ghrelin, Signal Transduction
PLoS ONE
Date: Mar. 06, 2009
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