Fig. 6.

Different steps involving Mmp14 and Itgb1 during MEC invasion/branching in a collagen 1 microenvironment. (A) Non-proteolytic activity of MMP14 is involved in mammary epithelial cell sorting in a CL-1 microenvironment (Mori et al., 2009). The relationship between Mmp14 expression and MEC sorting. Whereas MECs expressing full-length Mmp14 (FL-Mmp14) or the catalytic domain-deleted mutant (dCAT) sort to the invasive front, the hemopexin domain-deleted mutant (dPEX) or MECs with silenced Mmp14 expression do not. (B) Proteolytic activity of Mmp14 is required for MECs to invade/branch in dense CL-1 (Alcaraz et al., 2011). MECs need to degrade collagen 1 to generate a path for invasion/branching in dense collagen. Mmp14 is at the hub of this proteolytic activity for collagen degradation. (C) The association between Mmp14 and Itgb1 during MEC invasion/branching in a sparse CL-1 microenvironment. Whereas MECs do not need MMP activity for invasion/branching in sparse CL-1 gels, Mmp14 itself is required. Specifically, Mmp14 association with Itgb1 is necessary for MEC invasion/branching. Expressing FL-MMP14 or dCAT/dPEX in Mmp14-silenced MECs results in restoration of Itgb1 levels and activity to facilitate branching. Expression of the catalytic domain-deleted mutant (dCAT) was unable to rescue branching and the activation of Itgb1 in sparse CL-1 gels when the catalytic domain is absent. These events (from A to C) suggest that cells use different functions and domains of Mmp14 in a context-dependent manner during branching in collagenous microenvironments.