Membrane type-1 matrix metalloproteinase activity is regulated by the endocytic collagen receptor Endo180.
The molecular interactions leading to organised, controlled extracellular matrix degradation are of central importance during growth, development and tissue repair, and when deregulated contribute to disease processes including cancer cell invasion. There are two major pathways for collagen degradation: one dependent on secreted and membrane-bound collagenases, the other on receptor-mediated collagen internalisation and intracellular processing. Despite the established importance of both pathways, the functional interaction between them is largely unknown. We demonstrate here, that the collagen internalisation receptor Endo180 (also known as CD280, uPARAP, MRC2) is a novel regulator of membrane-bound matrix metalloproteinase (MT1-MMP) activity, MT1-MMP-dependent MMP-2 activation and urokinase plasminogen activator (uPA) activity. We show close correlation between Endo180 expression, collagen accumulation and regulation of MT1-MMP cell-surface localisation and activity. We directly demonstrate, using collagen inhibition studies and non-collagen-binding mutants of Endo180, that the molecular mechanism underlying this regulation is the ability of Endo180 to bind and/or internalise collagens, rather than by acting as an interaction partner for pro-uPA and its receptor uPAR. These studies strongly support a functional interaction between two distinct collagen degradation pathways, define a novel mechanism regulating MT1-MMP activity and might have important implications for organised collagen clearance in the pericellular environment.
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
Georgia
G
Messaritou
Lucy
L
East
Christian
C
Roghi
Clare M
CM
Isacke
Helen
H
Yarwood
D002460:Cell Line; D003094:Collagen / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004705:Endocytosis; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
C408294:Endo180; D034741:RNA, Small Interfering; D011975:Receptors, Mitogen; D055293:Receptors, Urokinase Plasminogen Activator; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14