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 Blood, 15 October 2008, Vol. 112, No. 8, pp. 3217-3226.
Prepublished online as a Blood First Edition Paper on July 28, 2008; DOI 10.1182/blood-2008-02-139394.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells

María Yañez-Mó1,2, Olga Barreiro2, Pilar Gonzalo2, Alicia Batista3, Diego Megías4, Laura Genís2, Norman Sachs5, Mónica Sala-Valdés2, Miguel A. Alonso3, María C. Montoya4, Arnoud Sonnenberg5, Alicia G. Arroyo2, and Francisco Sánchez-Madrid1,2

1 Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain; 2 Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; 3 Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, Madrid, Spain; 4 Centro Nacional de Investigaciones Oncológicas, Madrid, Spain; and 5 Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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 {alpha}3β1 integrin. Biochemical and FRET analyses show that MT1-MMP, through its hemopexin domain, associates tightly with CD151, thus forming {alpha}3β1 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 {alpha}3β1. 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.


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