Abstract
VE-cadherin is an endothelial-specific cadherin that plays a central role in vascular barrier function and angiogenesis. The cytoplasmic domain of VE-cadherin is linked to the cytoskeleton through interactions with the armadillo family proteins beta-catenin and plakoglobin. Growing evidence indicates that beta-catenin and plakoglobin play important roles in epithelial growth and morphogenesis. To test the role of these proteins in vascular cells, a replication-deficient retroviral system was used to express intercellular junction proteins and mutants in the human dermal microvascular endothelial cell line (HMEC-1). A mutant VE-cadherin lacking an adhesive extracellular domain disrupted endothelial barrier function and inhibited endothelial growth. In contrast, expression of exogenous plakoglobin or metabolically stable mutants of beta-catenin stimulated HMEC-1 cell growth, which suggests that the beta-catenin signaling pathway was active in HMEC-1 cells. This possibility was supported by the finding that a dominant-negative mutant of the transcription factor TCF-4, designed to inhibit beta-catenin signaling, also inhibited HMEC-1 cell growth. These observations suggest that intercellular junction proteins function as components of an adhesion and signaling system that regulates vascular barrier function and growth.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antigens, CD
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Cadherins / genetics
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Cadherins / metabolism*
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Cadherins / pharmacology
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Capillary Permeability / drug effects
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Capillary Permeability / physiology*
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Cell Division / drug effects
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Cell Division / physiology
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Cell Line
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Cytoskeletal Proteins / pharmacology
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Desmoplakins
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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Gene Expression
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Genes, Dominant
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Genetic Vectors / genetics
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Humans
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Mutagenesis, Site-Directed
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Protein Structure, Tertiary / physiology
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RNA, Messenger / metabolism
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Retroviridae / genetics
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Signal Transduction / drug effects
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Signal Transduction / physiology
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TCF Transcription Factors
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Trans-Activators / pharmacology
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Transcription Factor 7-Like 2 Protein
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / pharmacology
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Transfection
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beta Catenin
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gamma Catenin
Substances
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Antigens, CD
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CTNNB1 protein, human
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Cadherins
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Cytoskeletal Proteins
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Desmoplakins
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RNA, Messenger
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TCF Transcription Factors
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TCF7L2 protein, human
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Trans-Activators
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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beta Catenin
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cadherin 5
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gamma Catenin