Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Blotting, Western
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Cell Line
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Cell Line, Tumor
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Cell Movement / drug effects
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Cells, Cultured
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Gene Expression Profiling
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / immunology
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Hyaluronan Receptors / metabolism*
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Immunoprecipitation
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Mice
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Mice, SCID
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Neoplasms, Experimental / blood supply
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Neoplasms, Experimental / pathology
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / prevention & control
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Neovascularization, Physiologic / physiology*
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Protein Binding
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / physiology*
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Transfection
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / immunology
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Substances
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Antibodies, Monoclonal
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CD44v6 antigen
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Hyaluronan Receptors
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Vascular Endothelial Growth Factor A
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Proto-Oncogene Proteins c-met
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Vascular Endothelial Growth Factor Receptor-2