VE-cadherin is a critical endothelial regulator of TGF-beta signalling.
VE-cadherin is an endothelial-specific transmembrane protein concentrated at cell-to-cell adherens junctions. Besides promoting cell adhesion and controlling vascular permeability, VE-cadherin transfers intracellular signals that contribute to vascular stabilization. However, the molecular mechanism by which VE-cadherin regulates vascular homoeostasis is still poorly understood. Here, we report that VE-cadherin expression and junctional clustering are required for optimal transforming growth factor-beta (TGF-beta) signalling in endothelial cells (ECs). TGF-beta antiproliferative and antimigratory responses are increased in the presence of VE-cadherin. ECs lacking VE-cadherin are less responsive to TGF-beta/ALK1- and TGF-beta/ALK5-induced Smad phosphorylation and target gene transcription. VE-cadherin coimmunoprecipitates with all the components of the TGF-beta receptor complex, TbetaRII, ALK1, ALK5 and endoglin. Clustered VE-cadherin recruits TbetaRII and may promote TGF-beta signalling by enhancing TbetaRII/TbetaRI assembly into an active receptor complex. Taken together, our data indicate that VE-cadherin is a positive and EC-specific regulator of TGF-beta signalling. This suggests that reduction or inactivation of VE-cadherin may contribute to progression of diseases where TGF-beta signalling is impaired.
Rudini
Noemi
N
Vascular Biology Unit, FIRC Institute of Molecular Oncology, Milan, Italy.
Felici
Angelina
A
Giampietro
Costanza
C
Lampugnani
MariaGrazia
M
Corada
Monica
M
Swirsding
Kendra
K
Garrè
Massimiliano
M
Liebner
Stefan
S
Letarte
Michelle
M
ten Dijke
Peter
P
Dejana
Elisabetta
E
D030301:Activin Receptors, Type II / Q000378:metabolism; D000482:Allantois / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000172:deficiency / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000099152:Cadherin 5
D030301:Activin Receptors, Type II; D015703:Antigens, CD; D015820:Cadherins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D000099152:Cadherin 5; C425364:ACVRL1 protein, human; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse