The phosphoinositide 3-kinase-Akt signaling pathway is essential to many biological processes, including cell proliferation, survival, metabolism, and angiogenesis, under pathophysiological conditions. Although 3-phosphoinositide-dependent kinase 1 (PDK1) is a primary activator of Akt at the plasma membrane, the optimal activation mechanism remains unclear. We report that adhesion molecule with IgG-like domain 2 (AMI GO2) is a novel scaffold protein that regulates PDK1 membrane localization and Akt activation. Loss of AMI GO2 in endothelial cells (ECs) led to apoptosis and inhibition of angiogenesis with Akt inactivation. Amino acid residues 465-474 in AMI GO2 directly bind to the PDK1 pleckstrin homology domain. A synthetic peptide containing the AMI GO2 465-474 residues abrogated the AMI GO2-PDK1 interaction and Akt activation. Moreover, it effectively suppressed pathological angiogenesis in murine tumor and oxygen-induced retinopathy models. These results demonstrate that AMI GO2 is an important regulator of the PDK1-Akt pathway in ECs and suggest that interference of the PDK1-AMI GO2 interaction might be a novel pharmaceutical target for designing an Akt pathway inhibitor.
Bibliographical noteFunding Information:
funded by MEST (grant NRF-2011-0019267). This work was also supported by the Mid-career Researcher Program (grant NRF-2013R1A2A2A01068963) through an NRF grant funded by MEST.
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (MEST; grants NRF-2015R1A2A1A05001859 and NRF-2013M3A9B6046563) and by the Bio and Medical Technology Development Program of the NRF
© 2015 Park et al.
All Science Journal Classification (ASJC) codes
- Cell Biology