MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells.
MT1-MMP plays a key role in endothelial function, as underscored by the angiogenic defects found in MT1-MMP deficient mice. We have studied the molecular interactions that underlie the functional regulation of MT1-MMP. At lateral endothelial cell junctions, MT1-MMP colocalizes with tetraspanin CD151 (Tspan 24) and its associated partner alpha3beta1 integrin. Biochemical and FRET analyses show that MT1-MMP, through its hemopexin domain, associates tightly with CD151, thus forming alpha3beta1 integrin/CD151/MT1-MMP ternary complexes. siRNA knockdown of HUVEC CD151 expression enhanced MT1-MMP-mediated activation of MMP2, and the same activation was seen in ex vivo lung endothelial cells isolated from CD151-deficient mice. However, analysis of collagen degradation in these experimental models revealed a diminished MT1-MMP enzymatic activity in confined areas around the cell periphery. CD151 knockdown affected both MT1-MMP subcellular localization and its inclusion into detergent-resistant membrane domains, and prevented biochemical association of the metalloproteinase with the integrin alpha3beta1. These data provide evidence for a novel regulatory role of tetraspanin microdomains on the collagenolytic activity of MT1-MMP and indicate that CD151 is a key regulator of MT1-MMP in endothelial homeostasis.
Yañez-Mó
María
M
Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Barreiro
Olga
O
Gonzalo
Pilar
P
Batista
Alicia
A
Megías
Diego
D
Genís
Laura
L
Sachs
Norman
N
Sala-Valdés
Mónica
M
Alonso
Miguel A
MA
Montoya
María C
MC
Sonnenberg
Arnoud
A
Arroyo
Alicia G
AG
Sánchez-Madrid
Francisco
F
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D060185:Tetraspanin 24
D015703:Antigens, CD; C554715:CD151 protein, human; C554716:Cd151 protein, mouse; D039201:Integrin alpha3beta1; D060185:Tetraspanin 24; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14