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MT-MMPS as Regulators of Vessel Stability Associated with Angiogenesis.

Sounni NE, Paye A, Host L, Noël A - Front Pharmacol (2011)

Bottom Line: Our understanding of the nature of MT-MMP interaction with extracellular and cell surface molecules and their multiple roles in vessel walls and perivascular stroma may provide new insights into mechanisms underlying vascular cell-ECM interactions and cell fate decisions in pathological conditions.Regulation of vascular leakage by MT-MMP interactions with the ECM could also lead to novel targeting opportunities for drug delivery in tumor.This review will shed lights on the emerging roles of MT1-MMP and MT4-MMP in vascular system alterations associated with cancer progression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, University of Liege Liège, Belgium.

ABSTRACT
The development of vascular system depends on the coordinated activity of a number of distinct families of molecules including growth factors and their receptors, cell adhesion molecules, extracellular matrix (ECM) molecules, and proteolytic enzymes. Matrix metalloproteases (MMPs) are a family of ECM degrading enzymes required for both physiological and pathological angiogenesis. Increasing evidence, point to a direct role of membrane type-MMPs (MT-MMPs) in vascular system stabilization, maturation, and leakage. Our understanding of the nature of MT-MMP interaction with extracellular and cell surface molecules and their multiple roles in vessel walls and perivascular stroma may provide new insights into mechanisms underlying vascular cell-ECM interactions and cell fate decisions in pathological conditions. Regulation of vascular leakage by MT-MMP interactions with the ECM could also lead to novel targeting opportunities for drug delivery in tumor. This review will shed lights on the emerging roles of MT1-MMP and MT4-MMP in vascular system alterations associated with cancer progression.

No MeSH data available.


Related in: MedlinePlus

Structure and substrate specificity of MT1-MMP and MT4-MMP. The structure of MT1-MMP and MT4-MMP share the identical domain organization of most MMPs, including a signal sequence (SS), propeptide domain (pro), a zinc-containing catalytic domain (catalytic) with 37 identity (50% similarity), a hing region, and a hemopexin like domain (hemopexin). In addition, MT1-MMP and MT4-MMP are anchored to the cell surface through a hydrophobic a transmembrane domain (TM) and a GPI anchor, respectively. Both the transmembrane MT1-MMP and the GPI–MT4-MMP contain proprotein convertase recognition RXR/KR motif in the propeptide domain and a hydrophilic region also called stem region at the end of hemopexin like domain. Whereas MT1-MMP exhibits activity against many ECM and non-ECM components both in vitro and in vivo, MT4-MMP was found in vitro to have a minimal or no activity against ECM molecules. The substrates of MT4-MMP in vivo are not yet identified.
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Figure 1: Structure and substrate specificity of MT1-MMP and MT4-MMP. The structure of MT1-MMP and MT4-MMP share the identical domain organization of most MMPs, including a signal sequence (SS), propeptide domain (pro), a zinc-containing catalytic domain (catalytic) with 37 identity (50% similarity), a hing region, and a hemopexin like domain (hemopexin). In addition, MT1-MMP and MT4-MMP are anchored to the cell surface through a hydrophobic a transmembrane domain (TM) and a GPI anchor, respectively. Both the transmembrane MT1-MMP and the GPI–MT4-MMP contain proprotein convertase recognition RXR/KR motif in the propeptide domain and a hydrophilic region also called stem region at the end of hemopexin like domain. Whereas MT1-MMP exhibits activity against many ECM and non-ECM components both in vitro and in vivo, MT4-MMP was found in vitro to have a minimal or no activity against ECM molecules. The substrates of MT4-MMP in vivo are not yet identified.

Mentions: The ECM in the vascular wall contains a variety of molecules including collagens, elastic fibers, hyaluronan (HA), fibronectin, vitronectin, laminins, glycosaminoglycans (GAG), proteoglycans, and adhesive glycoproteins that provide structural and mechanical support to the cells. Vascular and perivascular cells are connected to major structural ECM components by cell surface receptors including integrin and non-integrin molecules (Kalluri, 2003; Davis and Senger, 2008). Interactions of these receptors with ECM molecules influence vascular cell shape, behavior, and the response to cytokines and growth factors (Boudreau and Jones, 1999). ECM remodeling in vascular wall or perivascular stroma involves several enzymes among which Matrix metalloproteases (MMPs) produced by endothelial, inflammatory, or malignant cells are key players. MMPs are a family of zinc endopeptidases composed of 24 currently known human enzymes that share several functional domains. MMPs are often referred to soluble (MMPs) or membrane type-MMPs (MT-MMPs) that are anchored to the cell surface through transmembrane domain or glycosylphosphatidylinositol (GPI) linker. For a description of the structure, function, and regulation of MT-MMPs, the reader is referred to previous reviews (Sounni and Noel, 2005; Sohail et al., 2008). MT1-MMP (membrane type 1-matrix metalloproteinase-1, also known as MMP-14) a MMP with transmembrane and cytoplasmic domains is a unique cell surface activator of pro-MMP2 through the formation of trimolecular complex with TIMP-2 (tissue inhibitor of metalloproteinases). In addition, MT1-MMP has a large number of substrates including ECM and non-ECM molecules (Figure 1). MT4-MMP however has a glycophosphatidylinositol anchor instead of the type-1 transmembrane and is a poor activator of pro-MMP2. Despite the high degree of similarity between its ectodomain structure and that of MT1-MMP, MT4-MMP has a restricted repertoire of substrates with no activity against collagens (Figure 1). Collagenases are the only known mammalian enzymes able of degrading triple-helical fibrillar collagen into distinctive 3/4 and 1/4 fragments. Collagenolytic MMPs including MMP1, MMP8, MMP13, MMP14/MT1-MMP play pivotal roles in multiple physiological and pathological processes involving extensive and aberrant collagenolysis. MMP-mediated collagen remodeling regulates tissue homeostasis and development through several mechanisms, such as the generation of space for cell migration, production of cryptic peptides with novel biological activity or activation of signaling molecules (Page-McCaw et al., 2007). Latest technological progresses have obviously advanced our consideration of MMPs as important modulators of the tumor microenvironment (Kessenbrock et al., 2010). Beside their capacity to remodel ECM, these enzymes mediate the release of ECM-associated growth factors such as VEGF, TGFβ as well as unmask cryptic sites within ECM molecules which can simulate malignant cells and endothelial cells to communicate and escape from homeostatic control (Rundhaug, 2005; Page-McCaw et al., 2007; Kessenbrock et al., 2010). However, the contribution of MMPs to vessel maturation and stabilization is an innovative emergent concept. Understanding the complex roles of MT-MMPs in vessel wall assembly and function in homeostasis or disease will open new avenues to maintain vessel stability and functionality. The present review will highlight the emerging roles of MT1-MMP and MT4-MMP in vascular cell fate and function during cancer progression.


MT-MMPS as Regulators of Vessel Stability Associated with Angiogenesis.

Sounni NE, Paye A, Host L, Noël A - Front Pharmacol (2011)

Structure and substrate specificity of MT1-MMP and MT4-MMP. The structure of MT1-MMP and MT4-MMP share the identical domain organization of most MMPs, including a signal sequence (SS), propeptide domain (pro), a zinc-containing catalytic domain (catalytic) with 37 identity (50% similarity), a hing region, and a hemopexin like domain (hemopexin). In addition, MT1-MMP and MT4-MMP are anchored to the cell surface through a hydrophobic a transmembrane domain (TM) and a GPI anchor, respectively. Both the transmembrane MT1-MMP and the GPI–MT4-MMP contain proprotein convertase recognition RXR/KR motif in the propeptide domain and a hydrophilic region also called stem region at the end of hemopexin like domain. Whereas MT1-MMP exhibits activity against many ECM and non-ECM components both in vitro and in vivo, MT4-MMP was found in vitro to have a minimal or no activity against ECM molecules. The substrates of MT4-MMP in vivo are not yet identified.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3108474&req=5

Figure 1: Structure and substrate specificity of MT1-MMP and MT4-MMP. The structure of MT1-MMP and MT4-MMP share the identical domain organization of most MMPs, including a signal sequence (SS), propeptide domain (pro), a zinc-containing catalytic domain (catalytic) with 37 identity (50% similarity), a hing region, and a hemopexin like domain (hemopexin). In addition, MT1-MMP and MT4-MMP are anchored to the cell surface through a hydrophobic a transmembrane domain (TM) and a GPI anchor, respectively. Both the transmembrane MT1-MMP and the GPI–MT4-MMP contain proprotein convertase recognition RXR/KR motif in the propeptide domain and a hydrophilic region also called stem region at the end of hemopexin like domain. Whereas MT1-MMP exhibits activity against many ECM and non-ECM components both in vitro and in vivo, MT4-MMP was found in vitro to have a minimal or no activity against ECM molecules. The substrates of MT4-MMP in vivo are not yet identified.
Mentions: The ECM in the vascular wall contains a variety of molecules including collagens, elastic fibers, hyaluronan (HA), fibronectin, vitronectin, laminins, glycosaminoglycans (GAG), proteoglycans, and adhesive glycoproteins that provide structural and mechanical support to the cells. Vascular and perivascular cells are connected to major structural ECM components by cell surface receptors including integrin and non-integrin molecules (Kalluri, 2003; Davis and Senger, 2008). Interactions of these receptors with ECM molecules influence vascular cell shape, behavior, and the response to cytokines and growth factors (Boudreau and Jones, 1999). ECM remodeling in vascular wall or perivascular stroma involves several enzymes among which Matrix metalloproteases (MMPs) produced by endothelial, inflammatory, or malignant cells are key players. MMPs are a family of zinc endopeptidases composed of 24 currently known human enzymes that share several functional domains. MMPs are often referred to soluble (MMPs) or membrane type-MMPs (MT-MMPs) that are anchored to the cell surface through transmembrane domain or glycosylphosphatidylinositol (GPI) linker. For a description of the structure, function, and regulation of MT-MMPs, the reader is referred to previous reviews (Sounni and Noel, 2005; Sohail et al., 2008). MT1-MMP (membrane type 1-matrix metalloproteinase-1, also known as MMP-14) a MMP with transmembrane and cytoplasmic domains is a unique cell surface activator of pro-MMP2 through the formation of trimolecular complex with TIMP-2 (tissue inhibitor of metalloproteinases). In addition, MT1-MMP has a large number of substrates including ECM and non-ECM molecules (Figure 1). MT4-MMP however has a glycophosphatidylinositol anchor instead of the type-1 transmembrane and is a poor activator of pro-MMP2. Despite the high degree of similarity between its ectodomain structure and that of MT1-MMP, MT4-MMP has a restricted repertoire of substrates with no activity against collagens (Figure 1). Collagenases are the only known mammalian enzymes able of degrading triple-helical fibrillar collagen into distinctive 3/4 and 1/4 fragments. Collagenolytic MMPs including MMP1, MMP8, MMP13, MMP14/MT1-MMP play pivotal roles in multiple physiological and pathological processes involving extensive and aberrant collagenolysis. MMP-mediated collagen remodeling regulates tissue homeostasis and development through several mechanisms, such as the generation of space for cell migration, production of cryptic peptides with novel biological activity or activation of signaling molecules (Page-McCaw et al., 2007). Latest technological progresses have obviously advanced our consideration of MMPs as important modulators of the tumor microenvironment (Kessenbrock et al., 2010). Beside their capacity to remodel ECM, these enzymes mediate the release of ECM-associated growth factors such as VEGF, TGFβ as well as unmask cryptic sites within ECM molecules which can simulate malignant cells and endothelial cells to communicate and escape from homeostatic control (Rundhaug, 2005; Page-McCaw et al., 2007; Kessenbrock et al., 2010). However, the contribution of MMPs to vessel maturation and stabilization is an innovative emergent concept. Understanding the complex roles of MT-MMPs in vessel wall assembly and function in homeostasis or disease will open new avenues to maintain vessel stability and functionality. The present review will highlight the emerging roles of MT1-MMP and MT4-MMP in vascular cell fate and function during cancer progression.

Bottom Line: Our understanding of the nature of MT-MMP interaction with extracellular and cell surface molecules and their multiple roles in vessel walls and perivascular stroma may provide new insights into mechanisms underlying vascular cell-ECM interactions and cell fate decisions in pathological conditions.Regulation of vascular leakage by MT-MMP interactions with the ECM could also lead to novel targeting opportunities for drug delivery in tumor.This review will shed lights on the emerging roles of MT1-MMP and MT4-MMP in vascular system alterations associated with cancer progression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, University of Liege Liège, Belgium.

ABSTRACT
The development of vascular system depends on the coordinated activity of a number of distinct families of molecules including growth factors and their receptors, cell adhesion molecules, extracellular matrix (ECM) molecules, and proteolytic enzymes. Matrix metalloproteases (MMPs) are a family of ECM degrading enzymes required for both physiological and pathological angiogenesis. Increasing evidence, point to a direct role of membrane type-MMPs (MT-MMPs) in vascular system stabilization, maturation, and leakage. Our understanding of the nature of MT-MMP interaction with extracellular and cell surface molecules and their multiple roles in vessel walls and perivascular stroma may provide new insights into mechanisms underlying vascular cell-ECM interactions and cell fate decisions in pathological conditions. Regulation of vascular leakage by MT-MMP interactions with the ECM could also lead to novel targeting opportunities for drug delivery in tumor. This review will shed lights on the emerging roles of MT1-MMP and MT4-MMP in vascular system alterations associated with cancer progression.

No MeSH data available.


Related in: MedlinePlus