Mouse matrix metalloprotease-1a (Mmp1a) gives new insight into MMP function

Abstract

Matrix metalloprotease-1 (MMP1) has been implicated in many human disease processes, however the lack of a well characterized murine homologue has significantly limited the study of MMP1 and the development of MMP-targeted therapeutics. The discovery of murine Mmp1a in 2001, the functional mouse homologue of MMP1, offers a valuable tool for modeling MMP1-mediated processes in mice. Variation in physiologic expression levels of Mmp1a in mice as compared to MMP1 in humans highlights the importance of understanding the similarities and differences between the homologues. Recent studies have demonstrated tumor growth-, invasion-, and angiogenesis-promoting functions of Mmp1a in lung cancer models, consistent with the analogous functions observed for human MMP1. Biochemical investigations have shown that point mutations in the pro-domain of mouse Mmp1a weaken docking between the pro- and catalytic domains, generating an unstable zymogen primed for activation. The difficulty to effectively maintain Mmp1a in the zymogen form may account for the tight control of Mmp1a expression and reduced expression in normal tissue as compared to inflammatory states or cancer. This discovery raises important questions about the activation mechanisms and regulation of the MMP family in general.

Fig. 1

Homology of MMP1 and Mmp1a. A: Chromosomal location of MMP1 (upper) and Mmp1a (lower) in the MMP rich locus of humans and mice respectively. B: Percent similarity of mammalian MMP1 homologue protein sequences. Percentage determined by Clustal sequence alignment using the Meg Align program.

Fig. 2

Generalized schematic of MAP kinase signaling demonstrating the points of pathway activation for cancer models shown to overexpress Mmp1a.

Fig. 3

The prodomain of MMP1/Mmp1a. A: Sequence alignment of the human MMP1 (upper) and mouse Mmp1a (lower) prodomain (excluding the first 12 non-helix residues). The F70-L67 substitution is highlighted. Arrows illustrate cleavage sequence of pro-MMP1 activation. B: Cartoon representation of the MMP1/Mmp1a prodomain interaction with catalytic domain. Arrows illustrate cleavage sequence of pro-MMP1 activation. C: Structural model representing the prodomain (yellow) and catalytic domain (blue) of MMP1/Mmp1a. The hydrophobic interaction of human prodomain F⁷⁰ (green) and mouse L⁶⁷ (red) with catalytic domain H²²⁵S²²⁶S²²⁷ and F²³⁴P²³⁵ (green) are highlighted.