Individual Timp deficiencies differentially impact pro-MMP-2 activation.
Membrane-type matrix metalloproteinases (MT-MMPs) have emerged as key enzymes in tumor cell biology. The importance of MT1-MMP, in particular, is highlighted by its ability to activate pro-MMP-2 at the cell surface through the formation of a trimolecular complex comprised of MT1-MMP/tissue inhibitor...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2006
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| _version_ | 1797062839665426432 |
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| author | English, J Kassiri, Z Koskivirta, I Atkinson, S Di Grappa, M Soloway, P Nagase, H Vuorio, E Murphy, G Khokha, R |
| author_facet | English, J Kassiri, Z Koskivirta, I Atkinson, S Di Grappa, M Soloway, P Nagase, H Vuorio, E Murphy, G Khokha, R |
| author_sort | English, J |
| collection | OXFORD |
| description | Membrane-type matrix metalloproteinases (MT-MMPs) have emerged as key enzymes in tumor cell biology. The importance of MT1-MMP, in particular, is highlighted by its ability to activate pro-MMP-2 at the cell surface through the formation of a trimolecular complex comprised of MT1-MMP/tissue inhibitor of metalloproteinase-2 (TIMP-2)/pro-MMP-2. TIMPs 1-4 are physiological MMP inhibitors with distinct roles in the regulation of pro-MMP-2 processing. Here, we have shown that individual Timp deficiencies differentially affect MMP-2 processing using primary mouse embryonic fibroblasts (MEFs). Timp-3 deficiency accelerated pro-MMP-2 activation in response to both cytochalasin D and concanavalin A. Exogenous TIMP-2 and N-TIMP-3 inhibited this activation, whereas TIMP-3 containing matrix from wild-type MEFs did not rescue the enhanced MMP-2 activation in Timp-3(-/-) cells. Increased processing of MMP-2 did not arise from increased expression of MT1-MMP, MT2-MMP, or MT3-MMP or altered expression of TIMP-2 and MMP-2. To test whether increased MMP-2 processing in Timp-3(-/-) MEFs is dependent on TIMP-2, double deficient Timp-2(-/-)/-3(-/-) MEFs were used. In these double deficient cells, the cleavage of pro-MMP-2 to its intermediate form was substantially increased, but the subsequent cleavage of intermediate-MMP-2 to fully active form, although absent in Timp-2(-/-) MEFs, was detectable with combined Timp-2(-/-)/-3(-/-) deficiency. TIMP-4 associates with MMP-2 and MT1-MMP in a manner similar to TIMP-3, but its deletion had no effect on pro-MMP-2 processing. Thus, TIMP-3 provides an inherent regulation over the kinetics of pro-MMP-2 processing, serving at a level distinct from that of TIMP-2 and TIMP-4. |
| first_indexed | 2024-03-06T20:51:20Z |
| format | Journal article |
| id | oxford-uuid:37ae85cf-94b2-4733-aa65-1c2d5c224877 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:51:20Z |
| publishDate | 2006 |
| record_format | dspace |
| spelling | oxford-uuid:37ae85cf-94b2-4733-aa65-1c2d5c2248772022-03-26T13:45:29ZIndividual Timp deficiencies differentially impact pro-MMP-2 activation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:37ae85cf-94b2-4733-aa65-1c2d5c224877EnglishSymplectic Elements at Oxford2006English, JKassiri, ZKoskivirta, IAtkinson, SDi Grappa, MSoloway, PNagase, HVuorio, EMurphy, GKhokha, RMembrane-type matrix metalloproteinases (MT-MMPs) have emerged as key enzymes in tumor cell biology. The importance of MT1-MMP, in particular, is highlighted by its ability to activate pro-MMP-2 at the cell surface through the formation of a trimolecular complex comprised of MT1-MMP/tissue inhibitor of metalloproteinase-2 (TIMP-2)/pro-MMP-2. TIMPs 1-4 are physiological MMP inhibitors with distinct roles in the regulation of pro-MMP-2 processing. Here, we have shown that individual Timp deficiencies differentially affect MMP-2 processing using primary mouse embryonic fibroblasts (MEFs). Timp-3 deficiency accelerated pro-MMP-2 activation in response to both cytochalasin D and concanavalin A. Exogenous TIMP-2 and N-TIMP-3 inhibited this activation, whereas TIMP-3 containing matrix from wild-type MEFs did not rescue the enhanced MMP-2 activation in Timp-3(-/-) cells. Increased processing of MMP-2 did not arise from increased expression of MT1-MMP, MT2-MMP, or MT3-MMP or altered expression of TIMP-2 and MMP-2. To test whether increased MMP-2 processing in Timp-3(-/-) MEFs is dependent on TIMP-2, double deficient Timp-2(-/-)/-3(-/-) MEFs were used. In these double deficient cells, the cleavage of pro-MMP-2 to its intermediate form was substantially increased, but the subsequent cleavage of intermediate-MMP-2 to fully active form, although absent in Timp-2(-/-) MEFs, was detectable with combined Timp-2(-/-)/-3(-/-) deficiency. TIMP-4 associates with MMP-2 and MT1-MMP in a manner similar to TIMP-3, but its deletion had no effect on pro-MMP-2 processing. Thus, TIMP-3 provides an inherent regulation over the kinetics of pro-MMP-2 processing, serving at a level distinct from that of TIMP-2 and TIMP-4. |
| spellingShingle | English, J Kassiri, Z Koskivirta, I Atkinson, S Di Grappa, M Soloway, P Nagase, H Vuorio, E Murphy, G Khokha, R Individual Timp deficiencies differentially impact pro-MMP-2 activation. |
| title | Individual Timp deficiencies differentially impact pro-MMP-2 activation. |
| title_full | Individual Timp deficiencies differentially impact pro-MMP-2 activation. |
| title_fullStr | Individual Timp deficiencies differentially impact pro-MMP-2 activation. |
| title_full_unstemmed | Individual Timp deficiencies differentially impact pro-MMP-2 activation. |
| title_short | Individual Timp deficiencies differentially impact pro-MMP-2 activation. |
| title_sort | individual timp deficiencies differentially impact pro mmp 2 activation |
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