Emerging roles of MT‐MMPs in embryonic development

Abstract

Membrane-type matrix metalloproteinases (MT-MMPs) are cell membrane-tethered proteinases that belong to the family of the MMPs. Apart from their roles in degradation of the extracellular milieu, MT-MMPs are able to activate through proteolytic processing at the cell surface distinct molecules such as receptors, growth factors, cytokines, adhesion molecules and other pericellular proteins. Although most of the information regarding these enzymes comes from cancer studies, our current knowledge about their contribution in distinct developmental processes occurring in the embryo is limited. In this review, we want to summarize the involvement of MT-MMPs in distinct processes during embryonic morphogenesis, including cell migration and proliferation, epithelialmesenchymal transition, cell polarity and branching, axon growth and navigation, synapse formation, and angiogenesis. We also considered information about MT-MMP functions from studies assessed in pathological conditions and compared these data with those relevant for embryonic development.

Tiki proteins are substrates of membrane‐type matrix metalloproteinases

“…This study uncovers a novel regulation of TIKI2 proteins on the cell surface by MT‐MMPs MMP14, MMP15 and MMP16. MT‐MMPs play critical roles in development, homeostasis and diseases, such as cancer metastasis, by hydrolysing multiple protein substrates in the extracellular matrix and on the cell surface [27,28]. Our results suggest that MT‐MMPs may regulate Wnt signalling by hydrolysing and inactivating Tiki proteins on the cell surface.…”

De novo disruptive heterozygous MMP21 variants are potential predisposing genetic risk factors in Chinese Han heterotaxy children

“…As a highly orchestrated process, embryonic development is inseparable from timed expression and activation of protease/antiprotease systems [ 53 , 54 ]. MMPs are crucial in regulating vasculogenesis and epithelial-to-mesenchymal transition during organogenesis [ 55 ]. MMP21 is a zinc-dependent ECM remodeling endopeptidase involved in ECM degradation and embryonic development regulation [ 26 , 27 ].…”

Molecular Mechanisms Driven by MT4-MMP in Cancer Progression

“…However, its proteolytic activity has been shown to be significantly linked to its pro-metastatic activity, and the latter may explain certain aspects of its role in cancer progression (Figure 1B). For example, unlike most MT-MMPs, MT4-MMP hydrolyses very few ECM components [1], and it also exhibits characteristic sensitivity to TIMPS as well as inefficient activation of pro-MMP2, which may explain its singular role in promoting tumor progression.…”

“…Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases that are able to degrade and remodel the extracellular matrix (ECM) by the cleavage of distinct matrix components and also to lead to the proteolytic activation/inactivation of receptors, growth factors, adhesion molecules, cytokines and other pericellular proteins [1,2]. Included within the MMPs family are the Membrane-Type Matrix Metalloproteinases (MT-MMPs) which are anchored to the cell membrane either by a type I transmembrane domain (MT1-MMP/MMP-14, MT2-MMP/MMP-15, MT3-MMP/MMP-16, and MT5-MMP/MMP-24) or via a glycosylphosphatidylinositol (GPI)-anchor (MT4-MMP/MMP-17 and MT6-MMP/MMP-25) [1,3,4].…”

“…For instance, its hemopexin domain only displays a 40% similarity with the same domain of the other family members [7]. This feature may explain the specificity and exclusivity of the substrates to be cleaved by MT4-MMP [1,8]. In fact, only a limited number of substrates have been identified for this endopeptidase, including matrix and matricellular proteins such as fibrin/fibrinogen, gelatin [8], osteopontin [9], periostin [10], proteases like ADAMTS-4 [11,12], and membrane proteins as αM-integrin [13], Pro-TNFα [8] and LRP [14].…”