Sandbox Reserved 1125: Difference between revisions

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== Regulation by inhibitors ==

Petites info Chrichri:

<font=MMP activity may subsequently be regulated by the action of inhibitors, notably the tissue inhibitors of MMPs (TIMPs) - TIMP-1, TIMP-2, TIMP-3 and TIMP-4 - and the serum panproteinase inhibitor α2 macroglobulin (Baker et al., 2002) The TIMPs are six-loop disulphide-bonded proteins forming two domains. They interact via their N-terminal three disulphide-bonded loops with the active site cleft of the catalytic domain, although significant interactions of the hemopexin-like domains of MMP-2 and MMP-9 with the C-terminal domains of TIMPs appear to have specific biological relevance. The other MMP domains have distinct functions, such as as exosites for substrate interactions, e.g. the hemopexin-like domains of MMP-1, MMP-8, MMP-13, MMP-14, MMP-16 and MMP-18 are essential for their ability to cleave fibrillar collagens and the fibronectin-like domains of MMP-2 and MMP-9 confer their binding to denatured collagen substrates. The hemopexin-like domain of MMP-14 can homodimerise in order to promote its clustering at the cell surface, a property that promotes its activity. The hemopexin-like domain confers the ability to interact with other extracellular matrix components and cell adhesion molecules and may be of significance in the determination of specific pericellular locations of individual MMPs.

<font color='red'>MMP activity may subsequently be regulated by the action of inhibitors, notably the tissue inhibitors of MMPs (TIMPs) - TIMP-1, TIMP-2, TIMP-3 and TIMP-4 - and the serum panproteinase inhibitor α2 macroglobulin (Baker et al., 2002) The TIMPs are six-loop disulphide-bonded proteins forming two domains. They interact via their N-terminal three disulphide-bonded loops with the active site cleft of the catalytic domain, although significant interactions of the hemopexin-like domains of MMP-2 and MMP-9 with the C-terminal domains of TIMPs appear to have specific biological relevance. The other MMP domains have distinct functions, such as as exosites for substrate interactions, e.g. the hemopexin-like domains of MMP-1, MMP-8, MMP-13, MMP-14, MMP-16 and MMP-18 are essential for their ability to cleave fibrillar collagens and the fibronectin-like domains of MMP-2 and MMP-9 confer their binding to denatured collagen substrates. The hemopexin-like domain of MMP-14 can homodimerise in order to promote its clustering at the cell surface, a property that promotes its activity. The hemopexin-like domain confers the ability to interact with other extracellular matrix components and cell adhesion molecules and may be of significance in the determination of specific pericellular locations of individual MMPs.

The MMPs are regulated at the transcriptional and post-transcriptional levels, as well as by activation, inhibition and cell/ECM localization, which allows tissue-specific spatial and temporal patterns of functional activity. Expression levels may be modulated by different cytokines, growth factors, hormones, extracellular matrix interactions and cytoskeletal changes through specific elements in the MMP promoters governing transcriptional regulation. Sequestration of the secreted MMPs in Golgi vesicles has been described for many stimulated cells, as has storage of MMP-8 and MMP-9 in the secretory granules of PMN leucocytes. The membrane-associated MMPs appear to have distinct trafficking pathways to specific sites at the cell surface. Association of some MMPs with integrins and other cell surface receptors has been described, e.g. MMP-1-integrin-α2β1, MMP-2-integrin-αVβ3, MMP-14-integrin-α2β1/αVβ3, MMP-7-CD44 and MMP-9-CD44. Many MMPs bind to specific ECM components (see above). With the exception of very rapidly remodeling tissues, extracellular levels of MMPs tend to be quite low, and unambiguous immunohistochemical detection is challenging.

The four TIMPs act as a further level of extracellular regulation and also have specific patterns of gene regulation and tissue-specific expression. TIMP-3 is unusual in that it is largely sequestered into the extracellular matrix or at the cell surface via heparan sulphate proteoglycans. Individual TIMPs differ in their ability to inhibit different MMPs; TIMP-1 is a poor inhibitor of MMP-14, MMP-16 and MMP-19. In addition there are specific interactions of TIMP-1 with proMMP-9, of TIMP-2 with proMMP-2 and of TIMP-3 with both proMMP-2 and proMMP-9 by binding through their three C-terminal disulphide-bonded loops, which allows complexes of the inactive MMPs to be formed, as well as giving very tight-binding active enzyme complexes. The true significance of this has only been elucidated for proMMP-2, where the TIMP-2 complex allows binding of the MMP to MMP-14 at the cell surface, promoting its activation and potentially focusing proteolysis to specific sites. The activation of proMMPs in general is probably strictly pericellular, e.g. where plasmin, generated by the activity of urokinase-type plasminogen activator, is an initiator of activation cascades. If there is an excess of TIMPs and serine proteinase inhibitors in the environment, these may also confine activity to the local environment. There is a further level of regulation of the MMPs through clearance by endocytosis. Little is known of the fate of most MMP-TIMP complexes, but complexes with α2 macroglobulin are thought to be endocytosed after binding to the low density lipoprotein receptor related protein (LRP). Thrombospondin 2 modulates both MMP-9-TIMP-1 and MMP-2 internalisation via LRP. The membrane-associated proteinase MMP-14 is endocytosed via clathrin- and nonclathrin-mediated pathways and may recycle to the cell surface in some situations. The other MT-MMPs probably have similar properties.</font><ref>PMID:12235282</ref>

The four TIMPs act as a further level of extracellular regulation and also have specific patterns of gene regulation and tissue-specific expression. TIMP-3 is unusual in that it is largely sequestered into the extracellular matrix or at the cell surface via heparan sulphate proteoglycans. Individual TIMPs differ in their ability to inhibit different MMPs; TIMP-1 is a poor inhibitor of MMP-14, MMP-16 and MMP-19. In addition there are specific interactions of TIMP-1 with proMMP-9, of TIMP-2 with proMMP-2 and of TIMP-3 with both proMMP-2 and proMMP-9 by binding through their three C-terminal disulphide-bonded loops, which allows complexes of the inactive MMPs to be formed, as well as giving very tight-binding active enzyme complexes. The true significance of this has only been elucidated for proMMP-2, where the TIMP-2 complex allows binding of the MMP to MMP-14 at the cell surface, promoting its activation and potentially focusing proteolysis to specific sites. The activation of proMMPs in general is probably strictly pericellular, e.g. where plasmin, generated by the activity of urokinase-type plasminogen activator, is an initiator of activation cascades. If there is an excess of TIMPs and serine proteinase inhibitors in the environment, these may also confine activity to the local environment. There is a further level of regulation of the MMPs through clearance by endocytosis. Little is known of the fate of most MMP-TIMP complexes, but complexes with α2 macroglobulin are thought to be endocytosed after binding to the low density lipoprotein receptor related protein (LRP). Thrombospondin 2 modulates both MMP-9-TIMP-1 and MMP-2 internalisation via LRP. The membrane-associated proteinase MMP-14 is endocytosed via clathrin- and nonclathrin-mediated pathways and may recycle to the cell surface in some situations. The other MT-MMPs probably have similar properties.

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 == Regulation by inhibitors ==
 Petites info Chrichri:
-<font=MMP activity may subsequently be regulated by the action of inhibitors, notably the tissue inhibitors of MMPs (TIMPs) - TIMP-1, TIMP-2, TIMP-3 and TIMP-4 - and the serum panproteinase inhibitor α2 macroglobulin (Baker et al., 2002) The TIMPs are six-loop disulphide-bonded proteins forming two domains. They interact via their N-terminal three disulphide-bonded loops with the active site cleft of the catalytic domain, although significant interactions of the hemopexin-like domains of MMP-2 and MMP-9 with the C-terminal domains of TIMPs appear to have specific biological relevance. The other MMP domains have distinct functions, such as as exosites for substrate interactions, e.g. the hemopexin-like domains of MMP-1, MMP-8, MMP-13, MMP-14, MMP-16 and MMP-18 are essential for their ability to cleave fibrillar collagens and the fibronectin-like domains of MMP-2 and MMP-9 confer their binding to denatured collagen substrates. The hemopexin-like domain of MMP-14 can homodimerise in order to promote its clustering at the cell surface, a property that promotes its activity. The hemopexin-like domain confers the ability to interact with other extracellular matrix components and cell adhesion molecules and may be of significance in the determination of specific pericellular locations of individual MMPs.
+<font color='red'>MMP activity may subsequently be regulated by the action of inhibitors, notably the tissue inhibitors of MMPs (TIMPs) - TIMP-1, TIMP-2, TIMP-3 and TIMP-4 - and the serum panproteinase inhibitor α2 macroglobulin (Baker et al., 2002) The TIMPs are six-loop disulphide-bonded proteins forming two domains. They interact via their N-terminal three disulphide-bonded loops with the active site cleft of the catalytic domain, although significant interactions of the hemopexin-like domains of MMP-2 and MMP-9 with the C-terminal domains of TIMPs appear to have specific biological relevance. The other MMP domains have distinct functions, such as as exosites for substrate interactions, e.g. the hemopexin-like domains of MMP-1, MMP-8, MMP-13, MMP-14, MMP-16 and MMP-18 are essential for their ability to cleave fibrillar collagens and the fibronectin-like domains of MMP-2 and MMP-9 confer their binding to denatured collagen substrates. The hemopexin-like domain of MMP-14 can homodimerise in order to promote its clustering at the cell surface, a property that promotes its activity. The hemopexin-like domain confers the ability to interact with other extracellular matrix components and cell adhesion molecules and may be of significance in the determination of specific pericellular locations of individual MMPs.
 The MMPs are regulated at the transcriptional and post-transcriptional levels, as well as by activation, inhibition and cell/ECM localization, which allows tissue-specific spatial and temporal patterns of functional activity. Expression levels may be modulated by different cytokines, growth factors, hormones, extracellular matrix interactions and cytoskeletal changes through specific elements in the MMP promoters governing transcriptional regulation. Sequestration of the secreted MMPs in Golgi vesicles has been described for many stimulated cells, as has storage of MMP-8 and MMP-9 in the secretory granules of PMN leucocytes. The membrane-associated MMPs appear to have distinct trafficking pathways to specific sites at the cell surface. Association of some MMPs with integrins and other cell surface receptors has been described, e.g. MMP-1-integrin-α2β1, MMP-2-integrin-αVβ3, MMP-14-integrin-α2β1/αVβ3, MMP-7-CD44 and MMP-9-CD44. Many MMPs bind to specific ECM components (see above). With the exception of very rapidly remodeling tissues, extracellular levels of MMPs tend to be quite low, and unambiguous immunohistochemical detection is challenging.
+The four TIMPs act as a further level of extracellular regulation and also have specific patterns of gene regulation and tissue-specific expression. TIMP-3 is unusual in that it is largely sequestered into the extracellular matrix or at the cell surface via heparan sulphate proteoglycans. Individual TIMPs differ in their ability to inhibit different MMPs; TIMP-1 is a poor inhibitor of MMP-14, MMP-16 and MMP-19. In addition there are specific interactions of TIMP-1 with proMMP-9, of TIMP-2 with proMMP-2 and of TIMP-3 with both proMMP-2 and proMMP-9 by binding through their three C-terminal disulphide-bonded loops, which allows complexes of the inactive MMPs to be formed, as well as giving very tight-binding active enzyme complexes. The true significance of this has only been elucidated for proMMP-2, where the TIMP-2 complex allows binding of the MMP to MMP-14 at the cell surface, promoting its activation and potentially focusing proteolysis to specific sites. The activation of proMMPs in general is probably strictly pericellular, e.g. where plasmin, generated by the activity of urokinase-type plasminogen activator, is an initiator of activation cascades. If there is an excess of TIMPs and serine proteinase inhibitors in the environment, these may also confine activity to the local environment. There is a further level of regulation of the MMPs through clearance by endocytosis. Little is known of the fate of most MMP-TIMP complexes, but complexes with α2 macroglobulin are thought to be endocytosed after binding to the low density lipoprotein receptor related protein (LRP). Thrombospondin 2 modulates both MMP-9-TIMP-1 and MMP-2 internalisation via LRP. The membrane-associated proteinase MMP-14 is endocytosed via clathrin- and nonclathrin-mediated pathways and may recycle to the cell surface in some situations. The other MT-MMPs probably have similar properties.</font><ref>PMID:12235282</ref>
-The four TIMPs act as a further level of extracellular regulation and also have specific patterns of gene regulation and tissue-specific expression. TIMP-3 is unusual in that it is largely sequestered into the extracellular matrix or at the cell surface via heparan sulphate proteoglycans. Individual TIMPs differ in their ability to inhibit different MMPs; TIMP-1 is a poor inhibitor of MMP-14, MMP-16 and MMP-19. In addition there are specific interactions of TIMP-1 with proMMP-9, of TIMP-2 with proMMP-2 and of TIMP-3 with both proMMP-2 and proMMP-9 by binding through their three C-terminal disulphide-bonded loops, which allows complexes of the inactive MMPs to be formed, as well as giving very tight-binding active enzyme complexes. The true significance of this has only been elucidated for proMMP-2, where the TIMP-2 complex allows binding of the MMP to MMP-14 at the cell surface, promoting its activation and potentially focusing proteolysis to specific sites. The activation of proMMPs in general is probably strictly pericellular, e.g. where plasmin, generated by the activity of urokinase-type plasminogen activator, is an initiator of activation cascades. If there is an excess of TIMPs and serine proteinase inhibitors in the environment, these may also confine activity to the local environment. There is a further level of regulation of the MMPs through clearance by endocytosis. Little is known of the fate of most MMP-TIMP complexes, but complexes with α2 macroglobulin are thought to be endocytosed after binding to the low density lipoprotein receptor related protein (LRP). Thrombospondin 2 modulates both MMP-9-TIMP-1 and MMP-2 internalisation via LRP. The membrane-associated proteinase MMP-14 is endocytosed via clathrin- and nonclathrin-mediated pathways and may recycle to the cell surface in some situations. The other MT-MMPs probably have similar properties.
 <scene name='71/719866/Timp1/1'>TIMP</scene>