2. Academic Validation
  3. AMIGO2, a novel membrane anchor of PDK1, controls cell survival and angiogenesis via Akt activation

AMIGO2, a novel membrane anchor of PDK1, controls cell survival and angiogenesis via Akt activation

  • J Cell Biol. 2015 Nov 9;211(3):619-37. doi: 10.1083/jcb.201503113.
Hyojin Park 1,  Sungwoon Lee 1,  Pravesh Shrestha 1,  Jihye Kim 1,  Jeong Ae Park 1,  Yeongrim Ko 1,  Young Ho Ban 1,  Dae-Young Park 2,  Sang-Jun Ha 1,  Gou Young Koh 2,  Victor Sukbong Hong 3,  Naoki Mochizuki 4,  Young-Myeong Kim 5,  Weontae Lee 1,  Young-Guen Kwon 6
Affiliations

Affiliations

  • 1 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
  • 2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
  • 3 College of Natural Sciences, Keimyung University, Daegu 42601, Republic of Korea.
  • 4 Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
  • 5 Vascular System Research Center, Kangwon National University, Chuncheon, Kangwon 24341, Republic of Korea.
  • 6 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea ygkwon@yonsei.ac.kr.
PMID: 26553931 DOI: 10.1083/jcb.201503113
Abstract

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 (AMIGO2) is a novel scaffold protein that regulates PDK1 membrane localization and Akt activation. Loss of AMIGO2 in endothelial cells (ECs) led to Apoptosis and inhibition of angiogenesis with Akt inactivation. Amino acid residues 465-474 in AMIGO2 directly bind to the PDK1 pleckstrin homology domain. A synthetic peptide containing the AMIGO2 465-474 residues abrogated the AMIGO2-PDK1 interaction and Akt activation. Moreover, it effectively suppressed pathological angiogenesis in murine tumor and oxygen-induced retinopathy models. These results demonstrate that AMIGO2 is an important regulator of the PDK1-Akt pathway in ECs and suggest that interference of the PDK1-AMIGO2 interaction might be a novel pharmaceutical target for designing an Akt pathway inhibitor.

Figures
Products