Abstract
Mutation of the tumor suppressor adenomatous polyposis coli (APC) is a key early event in the development of most colorectal tumors. APC promotes degradation of beta-catenin and thereby negatively regulates Wnt signaling, whereas mutated APCs present in colorectal tumor cells are defective in this activity. APC also stimulates the activity of the guanine nucleotide exchange factor Asef and regulates cell morphology and migration. Truncated mutant APCs constitutively activate Asef and induce aberrant migration of colorectal tumor cells. Furthermore, we have recently found that Asef and APC function downstream of hepatocyte growth factor and phosphatidylinositol 3-kinase. We show here that Asef is required for basic fibroblast growth factor- and vascular endothelial growth factor-induced endothelial cell migration. We further demonstrate that Asef is required for basic fibroblast growth factor- and vascular endothelial growth factor-induced microvessel formation. Furthermore, we show that the growth as well as vascularity of subcutaneously implanted tumors are markedly impaired in Asef(-/-) mice compared with wild-type mice. Thus, Asef plays a critical role in tumor angiogenesis and may be a promising target for cancer chemotherapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / metabolism*
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Animals
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Cell Movement*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / mortality*
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Endothelial Cells / metabolism*
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 2 / metabolism
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism*
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Hepatocyte Growth Factor / genetics
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Hepatocyte Growth Factor / metabolism
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Mice
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Mice, Knockout
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Rho Guanine Nucleotide Exchange Factors
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Signal Transduction / genetics
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Adenomatous Polyposis Coli Protein
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Guanine Nucleotide Exchange Factors
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Rho Guanine Nucleotide Exchange Factors
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Vascular Endothelial Growth Factor A
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Wnt Proteins
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beta Catenin
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vascular endothelial growth factor A, mouse
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Fibroblast Growth Factor 2
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Hepatocyte Growth Factor
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Phosphatidylinositol 3-Kinases