Cell Migration through Extracellular Matrix

Every so often, a paper comes along that brings clarity to an issue. Clarity is not necessarily a final resolution, but rather a conceptual framework for productively addressing that issue. Such a paper could be based on a breakthrough discovery, an intriguing observation, a flash of intuition , or a systematic analysis. An excellent example of the latter is in this issue of The Journal of Cell Biology (Hotary et al., 2000). With a deceptively simple experimental layout, Hotary et al. (2000) explore the relative role of soluble versus membrane-anchored matrix metal-loproteinases (MMP) in tissue morphogenesis. In their in vitro morphogenesis and matrix invasion models, the conclusion is clear cut: membrane-anchored (MT-MMPs), not soluble MMPs, effectively regulate cell migration through extracellular matrix and affect self-organization of cells into tubular structures (Fig. 1). Cell migration through the matrix is a key component of morphogenesis, i.e., how tissue or organs attain their shape. It is truly an invasive process, whereby cells move into and possibly colonize new territory, and that is why one can speak of cell invasion and morphogenesis in the same breath, and test them with the same assay (Hotary et al., 2000). According to their differentiated type, the migratory cells may give rise to new structures within the matrix they invaded, e.g., tubules, alveoli, or acini, shaping tissues and organs. It is evident, then, why we would like to know the molecular details of migration through the matrix: what motivates cells to migrate, how they do it, how is the process controlled. There is general agreement that MMPs are important in the execution of migration through the matrix and of invasion , based on abundant data correlating invasive phenomena with the presence of MMPs (Stetler-Stevenson et al., 1993; Werb, 1997). In recent years, mainly via isolation of gelatinolytic activities and homology cloning, the burgeoning protein family of MMPs has come to include, in man, close to 20 members (Table I). Several of these degrade collagens (Table I), the most abundant components of the extracellular matrix, though fine substrate specificity is still at issue (Koshikawa et al., 2000). The majority of MMPs are secreted proteins generally requiring activation for enzymatic activity. A few are true transmembrane proteins , the membrane-type metalloproteinases or MT-MMPs, which are expressed at the cell surface in activated form. Does the MMP structural diversity reflect functional redundancy or specialization? With their systematic expression of proteinases in …