CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells.
CD97, a membrane protein expressed at high levels on inflammatory cells and some carcinomas, is a member of the adhesion G protein-coupled receptor family, whose members have bipartite structures consisting of an extracellular peptide containing adhesion motifs noncovalently coupled to a class B 7-transmembrane domain. CD97alpha, the extracellular domain of CD97, contains 3 to 5 fibrillin class 1 epidermal growth factor (EGF)-like repeats, an Arg-Gly-Asp (RGD) tripeptide, and a mucin stalk. We show here that CD97alpha promotes angiogenesis in vivo as demonstrated with purified protein in a directed in vivo angiogenesis assay (DIVAA) and by enhanced vascularization of developing tumors expressing CD97. These data suggest that CD97 can contribute to angiogenesis associated with inflammation and tumor progression. Strong integrin alpha5beta1 interactions with CD97 have been identified, but alpha v beta3 also contributes to cell attachment. Furthermore, soluble CD97 acts as a potent chemoattractant for migration and invasion of human umbilical vein endothelial cells (HUVECs), and this function is integrin dependent. CD97 EGF-like repeat 4 is known to bind chondroitin sulfate. It was found that coengagement of alpha5beta1 and chondroitotin sulfate proteoglycan by CD97 synergistically initiates endothelial cell invasion. Integrin alpha5beta1 is the first high-affinity cellular counterreceptor that has been identified for a member within this family of adhesion receptors.
Wang
Tao
T
Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bldg 10, Rm 3B-43, Bethesda, MD 20892, USA.
Ward
Yvona
Y
Tian
Linhua
L
Lake
Ross
R
Guedez
Liliana
L
Stetler-Stevenson
William G
WG
Kelly
Kathleen
K
D000818:Animals; D015703:Antigens, CD; D002448:Cell Adhesion / Q000502:physiology; D002809:Chondroitin Sulfates / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009842:Oligopeptides / Q000235:genetics; D010641:Phenotype; D017434:Protein Structure, Tertiary; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D014471:Umbilical Veins / Q000166:cytology
C095004:ADGRE5 protein, human; D015703:Antigens, CD; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D043562:Receptors, G-Protein-Coupled; D004815:Epidermal Growth Factor; C047981:arginyl-glycyl-aspartic acid; D002809:Chondroitin Sulfates