Basal localization of MT1-MMP is essential for epithelial cell morphogenesis in 3D collagen matrix

During epithelial tubulogenesis in 3D collagen matrices, the membrane-anchored collagenase MT1-MMP has been shown to play an essential role. 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. Inert polarized epithelial cells predominantly localized MT1-MMP at the apical surface, whereas HGF treatment induced basal localization of MT1-MMP, and resultant collagen degradation. The basal localization of MT1-MMP requires the ecto-domains of the enzyme, as 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 basal MT1-MMP localization. Interestingly, however, the effect of TGFβ was found to be bi-phasic: it effectively inhibited basal localization at high doses, but promoted basal localization of MT1-MMP and tubulogenesis at lower doses. Taken together these data indicate that basal localization of MT1-MMP is a key factor promoting ECM degradation by polarized epithelial cells, and that this is an essential part of epithelial morphogenesis in 3D collagen.