Regulation of endothelial barrier function and growth by VE-cadherin, plakoglobin, and beta-catenin.
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.
Venkiteswaran
Kala
K
Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Xiao
Kanyan
K
Summers
Susan
S
Calkins
Cathárine C
CC
Vincent
Peter A
PA
Pumiglia
Kevin
K
Kowalczyk
Andrew P
AP
D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051180:Desmoplakins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D005799:Genes, Dominant; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D051176:beta Catenin; D051185:gamma Catenin; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D012333:RNA, Messenger; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D051185:gamma Catenin; D000099152:Cadherin 5; C495270:CTNNB1 protein, human; C544894:TCF7L2 protein, human