A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis.
A specific splice variant of the CD44 cell- surface protein family, CD44v6, has been shown to act as a coreceptor for the receptor tyrosine kinase c-Met on epithelial cells. Here we show that also on endothelial cells (ECs), the activity of c-Met is dependent on CD44v6. Furthermore, another receptor tyrosine kinase, VEGFR-2, is also regulated by CD44v6. The CD44v6 ectodomain and a small peptide mimicking a specific extracellular motif of CD44v6 or a CD44v6-specific antibody prevent CD44v6-mediated receptor activation. This indicates that the extracellular part of CD44v6 is required for interaction with c-Met or VEGFR-2. In the cytoplasm, signaling by activated c-Met and VEGFR-2 requires association of the CD44 carboxy-terminus with ezrin that couples CD44v6 to the cytoskeleton. CD44v6 controls EC migration, sprouting, and tubule formation induced by hepatocyte growth factor (HGF) or VEGF-A. In vivo the development of blood vessels from grafted EC spheroids and angiogenesis in tumors is impaired by CD44v6 blocking reagents, suggesting that the coreceptor function of CD44v6 for c-Met and VEGFR-2 is a promising target to block angiogenesis in pathologic conditions.
Tremmel
Martina
M
Forschungszentrum Karlsruhe, Institute for Toxicology and Genetics, Karlsruhe, Germany.
Matzke
Alexandra
A
Albrecht
Imke
I
Laib
Anna M
AM
Olaku
Vivienne
V
Ballmer-Hofer
Kurt
K
Christofori
Gerhard
G
Héroult
Mélanie
M
Augustin
Hellmut G
HG
Ponta
Helmut
H
Orian-Rousseau
Véronique
V
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; C112697:CD44v6 antigen; D018960:Hyaluronan Receptors; D042461:Vascular Endothelial Growth Factor A; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2