MT4-(MMP17) and MT6-MMP (MMP25), A unique set of membrane-anchored matrix metalloproteinases: properties and expression in cancer

Abstract

The process of cancer progression involves the action of multiple proteolytic systems, among which the family of matrix metalloproteinases (MMPs) play a pivotal role. The MMPs evolved to accomplish their proteolytic tasks in multiple cellular and tissue microenvironments including lipid rafts by incorporation and deletions of specific structural domains. The membrane typeMMPs (MT-MMPs) incorporated membrane anchoring domains that display these proteases at the cell surface, and thus they are optimal pericellular proteolytic machines. Two members of the MT-MMP subfamily, MMP-17 (MT4-MMP) and MMP-25 (MT6-MMP), are anchored to the plasma membrane via a glycosyl-phosphatidyl inositol (GPI) anchor, which confers these enzymes a unique set of regulatory and functional mechanisms that separates them from the rest of the MMP family. Discovered almost a decade ago, the body of work on GPI-MT-MMPs today is still surprisingly limited when compared to other MT-MMPs. However, new evidence shows that the GPI-MT-MMPs are highly expressed in human cancer, where they are associated with progression. Accumulating biochemical and functional evidence also highlights their distinct properties. In this review, we summarize the structural, biochemical, and biological properties of GPI-MT-MMPs and present an overview of their expression and role in cancer. We further discuss the potential implications of GPI-anchoring for enzyme function. Finally, we comment on the new scientific challenges that lie ahead to better understand the function and role in cancer of these intriguing but yet unique MMPs.

Efficient Glycosylphosphatidylinositol (GPI) Modification of Membrane Proteins Requires a C-terminal Anchoring Signal of Marginal Hydrophobicity

“…The matrix metalloproteinase MMP19 was initially annotated as a GPI-modified protein by similarity to other GPI-anchored members of the family, notably MMP17 and 25 (27), but was later reclassified as a secreted protein (28), and our data confirms this. The EFNA4 protein belongs to the Ephrin A family of receptor tyrosine kinase ligands.…”

Characterization of the Dimerization Interface of Membrane Type 4 (MT4)-Matrix Metalloproteinase

“…The presence of a GPI anchor confers a unique subcellular distribution and regulation to MT4-and MT6-MMP, setting them apart from the other MT-MMPs. Moreover, contrary to the transmembrane MT-MMPs, which are insensitive to TIMP-1 inhibition, the GPI-anchored MT-MMPs are similarly inhibited by both TIMP-1 and TIMP-2 (2)(3)(4)(5). However, like all MTMMPs, MT4-and MT6-MMP are produced in a latent inactive form that is activated by cleavage of an RXXR motif located between the pro-domain and the catalytic domain by furin-like convertases (2).…”

“…Although much information is available on the regulation and function of transmembrane MT-MMPs, there is a conspicuous paucity of knowledge on the GPI-anchored MT-MMPs. The GPI-MT-MMPs includes two enzymes, MT4-(MMP17) and MT6-MMP (MMP25), that share similar structural features and biochemical properties (2). The presence of a GPI anchor confers a unique subcellular distribution and regulation to MT4-and MT6-MMP, setting them apart from the other MT-MMPs.…”

Microarray-based Transcriptional and Epigenetic Profiling of Matrix Metalloproteinases, Collagens, and Related Genes in Cancer

“…Glycosylphosphatidylinositol-linked, lipid raft-associated MT4-MMP and MT6-MMP do not contribute to cell migration (37), and MMP-9 is normally secreted as a latent zymogen, which is not efficiently activated (38,39). As a result, the elevated expression of these individual MMPs cannot contribute significantly to the locomotion of non-migratory MCF-7 cells.…”