MT4-(MMP17) and MT6-MMP (MMP25), A unique set of membrane-anchored matrix metalloproteinases: properties and expression in cancer.
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 type-MMPs (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.
Sohail
Anjum
A
Department of Pathology, School of Medicine, and Proteases and Cancer Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Sun
Qing
Q
Zhao
Huiren
H
Bernardo
M Margarida
MM
Cho
Jin-Ah
JA
Fridman
Rafael
R
D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D058851:GPI-Linked Proteins; D006801:Humans; D053515:Matrix Metalloproteinase 17 / Q000502:physiology*; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology*
D058851:GPI-Linked Proteins; D053515:Matrix Metalloproteinase 17; D053504:Matrix Metalloproteinases, Membrane-Associated; C403928:matrix metalloproteinase 25