Basal localization of MT1-MMP is essential for epithelial cell morphogenesis in 3D collagen matrix.
The membrane-anchored collagenase membrane type 1 matrix metalloprotease (MT1-MMP) has been shown to play an essential role during epithelial tubulogenesis in 3D collagen matrices; however, its regulation during tubulogenesis is not understood. Here, we report that degradation of collagen in polarized epithelial cells is post-translationally regulated by changing the localization of MT1-MMP from the apical to the basal surface. MT1-MMP predominantly localizes at the apical surface in inert polarized epithelial cells, whereas treatment with HGF induced basal localization of MT1-MMP followed by collagen degradation. The basal localization of MT1-MMP requires the ectodomains of the enzyme because deletion of the MT-loop region or the hemopexin domain inhibited basal localization of the enzyme. TGFβ is a well-known inhibitor of tubulogenesis and our data indicate that its mechanism of inhibition is, at least in part, due to inhibition of MT1-MMP localization to the basal surface. Interestingly, however, the effect of TGFβ was found to be bi-phasic: at high doses it effectively inhibited basal localization of MT1-MMP, whereas at lower doses tubulogenesis and basal localization of MT1-MMP was promoted. Taken together, these data indicate that basal localization of MT1-MMP is a key factor promoting the degradation of extracellular matrix by polarized epithelial cells, and that this is an essential part of epithelial morphogenesis in 3D collagen.
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
Sarah A
SA
Weaver
Brit
B
Wolters
Noriko
N
Ito
Anna M
AM
Woskowicz
Kazuyo
K
Kaneko
Yasuyuki
Y
Shitomi
Motoharu
M
Seiki
Yoshifumi
Y
Itoh
D000818:Animals; D002462:Cell Membrane / Q000201:enzymology*; D002465:Cell Movement; D016764:Cell Polarity; D003094:Collagen / Q000378:metabolism*; D003470:Culture Media; D004285:Dogs; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D038081:Organogenesis; D021381:Protein Transport; D059748:Proteolysis
D003470:Culture Media; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D003094:Collagen; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
Collagen; Epithelial cells; MT1-MMP; TGFβ; Tubulogenesis