DIP2A functions as a FSTL1 receptor.
FSTL1 is an extracellular glycoprotein whose functional significance in physiological and pathological processes is incompletely understood. Recently, we have shown that FSTL1 acts as a muscle-derived secreted factor that is up-regulated by Akt activation and ischemic stress and that FSTL1 exerts favorable actions on the heart and vasculature. Here, we sought to identify the receptor that mediates the cellular actions of FSTL1. We identified DIP2A as a novel FSTL1-binding partner from the membrane fraction of endothelial cells. Co-immunoprecipitation assays revealed a direct physical interaction between FSTL1 and DIP2A. DIP2A was present on the cell surface of endothelial cells, and knockdown of DIP2A by small interfering RNA reduced the binding of FSTL1 to cells. In cultured endothelial cells, knockdown of DIP2A by small interfering RNA diminished FSTL1-stimulated survival, migration, and differentiation into network structures and inhibited FSTL1-induced Akt phosphorylation. In cultured cardiac myocytes, ablation of DIP2A reduced the protective actions of FSTL1 on hypoxia/reoxygenation-induced apoptosis and suppressed FSTL1-induced Akt phosphorylation. These data indicate that DIP2A functions as a novel receptor that mediates the cardiovascular protective effects of FSTL1.
Ouchi
Noriyuki
N
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Asaumi
Yasuhide
Y
Ohashi
Koji
K
Higuchi
Akiko
A
Sono-Romanelli
Saki
S
Oshima
Yuichi
Y
Walsh
Kenneth
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D038702:Follistatin-Related Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
D002352:Carrier Proteins; C481541:DIP2A protein, human; D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt