Sohail Anjum, Sun Qing, Zhao Huiren, Bernardo M Margarida, Cho Jin-Ah, Fridman Rafael
Department of Pathology, School of Medicine, and Proteases and Cancer Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Cancer Metastasis Rev. 2008 Jun;27(2):289-302. doi: 10.1007/s10555-008-9129-8.
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.
癌症进展过程涉及多种蛋白水解系统的作用，其中基质金属蛋白酶（MMPs）家族起着关键作用。MMPs通过特定结构域的整合和缺失，进化到在包括脂筏在内的多种细胞和组织微环境中完成其蛋白水解任务。膜型MMPs（MT-MMPs）整合了膜锚定结构域，使这些蛋白酶在细胞表面呈现，因此它们是最佳的细胞周围蛋白水解机器。MT-MMP亚家族的两个成员，MMP-17（MT4-MMP）和MMP-25（MT6-MMP），通过糖基磷脂酰肌醇（GPI）锚定在质膜上，这赋予这些酶一套独特的调节和功能机制，使其与MMP家族的其他成员区分开来。大约十年前被发现，与其他MT-MMPs相比，如今关于GPI-MT-MMPs的研究工作仍然惊人地有限。然而，新证据表明，GPI-MT-MMPs在人类癌症中高度表达，与癌症进展相关。越来越多的生化和功能证据也凸显了它们的独特性质。在本综述中，我们总结了GPI-MT-MMPs的结构、生化和生物学特性，并概述了它们在癌症中的表达和作用。我们进一步讨论了GPI锚定对酶功能的潜在影响。最后，我们对未来为更好理解这些有趣但独特的MMPs在癌症中的功能和作用所面临的新科学挑战进行了评论。
