AMI GO2, a novel membrane anchor of PDK1, controls cell survival and angiogenesis via Akt activation

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.