Inactivating Mutation of the Mouse Tissue Inhibitor of Metalloproteinases-2(Timp-2) Gene Alters ProMMP-2 Activation

Caterina, John J.; Yamada, Susan S.; Caterina, Nancy C.M.; Longenecker, Glenn; Holmbäck, Kenn; Shi, Joanne; Yermovsky, Audra E.; Engler, Jeffrey A.; Birkedal‐Hansen, Henning

doi:10.1074/jbc.m001271200

Cited by 134 publications

(125 citation statements)

References 26 publications

(28 reference statements)

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“…Special membrane type MMPs (MT-MMP) cleave this complex into the active form of MMP. 33 This immunohistochemical study showed the expression of TIMP-2 to be slightly increased in tumour cells compared to nonmalignant tissue. This finding supports the relevance of TIMP-2 in the activation of the MMPs.…”

Section: Discussionmentioning

confidence: 99%

Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2) in prostate cancer tissue

Brehmer

Biesterfeld²,

Jakse

2003

Prostate Cancer Prostatic Dis

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Matrix metalloproteinases (MMPs) have been implicated in progression and metastases of different tumours. The balance between the MMPs and their natural inhibitors (tissue inhibitors of matrix metalloproteinases; TIMP) seems to be an important factor related to this role. Here, the expression of MMP-2 and -9 along with TIMP-1 and -2 was examined in prostate cancer tissue. A total of 40 radical prostatectomy specimens were embedded in paraffin and immunohistochemical staining was performed to detect MMP-2 and -9, and TIMP-1 and -2. The immunoreactivity was assessed semiquantitively using routine light microscopy. The intensity of staining was correlated to preoperative PSA, T category, Gleason score and clinical parameters of the specimens. The imbalance of MMPs and TIMPs was recognised as a significant loss of TIMP-1 in malignant epithelium and an upregulation of MMPs. Palpable tumours (T2, T3) expressed significantly more MMP-2 and significantly less MMP-9 than T1c tumours. Our data are in accordance with other literature reports in that an imbalance of MMPs and TIMPs is found in malignant tumours. The observed imbalance of MMP and TIMP is mainly caused by a loss of TIMP-1. Furthermore, palpable tumours demonstrated significantly more MMP-2 and significantly less MMP-9 expression than nonpalpable tumours.

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Section: Discussionmentioning

confidence: 99%

Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2) in prostate cancer tissue

Brehmer

Biesterfeld²,

Jakse

2003

Prostate Cancer Prostatic Dis

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“…However, other study showed that TIMP-2 binds to active MT1-MMP but not to latent MT1-MMP (Hernandez-Barrantes et al, 2000). Fully functional TIMP-2 is essential for e cient activation of proMMP-2 both in vitro and in vivo (Caterina et al, 2000). However, the active 65-kDa MMP-2 can be inhibited by plasma membrane-bound TIMP-2 (Itoh et al, 1998).…”

Section: Paradox 2: Timps Regulate Pro-mmp Activation and Tumor Angiomentioning

confidence: 95%

Complex roles of tissue inhibitors of metalloproteinases in cancer

2002

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Matrix metalloproteinases (MMPs) is tightly associated with extracellular matrix (ECM) turnover, which plays a very active role in tumor invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) plays a critical role in the homeostasis of ECM by regulating the activity of MMPs. TIMPs are well-known for their ability to inhibit MMP activity thereby inhibiting tumor growth and metastasis. However, many evidences suggest that TIMPs are multifunctional proteins, which regulate cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis. These e ects may be through MMPdependent or MMP-independent pathways. Recent data indicate that TIMPs have many paradoxical roles in tumorigenesis. In particular, both inhibitory e ect and stimulatory e ect on tumorigenesis have been demonstrated in many animal models in which TIMPs were overexpressed in cancer cells or in mice. Elevated TIMP levels are reported in association with cancer progression and identi®ed as poor prognostic indicators in several human tumor types. Herein, we review the complex roles of TIMPs in cancer growth and metastasis.

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“…Despite the importance of TIMP-2 and integrin ␣v␤3 in the autoproteolytic activation of MMP-2 following MT1-MMPcleavage (10,33,47), these molecules are not likely to be involved in the complete activation of factor Xa-processed MMP-2. Full activation of MMP-2 was not affected in MCF-7 cells that express negligible amounts of TIMP-2 and HEK293F cells transfected with integrin ␣v small interfering RNA (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, trypsin-2-processed MMP-2 was obtained by incubating purified pro-MMP-2 with trypsin-2 under cell-free conditions (40). Therefore, autoproteolytic processing of trypsin-2-cleaved MMP-2 is not likely to occur, since cellular molecules, such as TIMP-2 and integrin ␣v␤3, may be required for the maturation of partially processed MMP-2 to its fully active form (10,12,33,47). This may explain the partial activation of trypsin-2-processed MMP-2 seen under cell-free conditions.…”

Section: Discussionmentioning

confidence: 99%

Regulatory Mechanism of Matrix Metalloprotease-2 Enzymatic Activity by Factor Xa and Thrombin

Koo

Park

Jeon³

et al. 2009

Journal of Biological Chemistry

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Matrix metalloprotease (MMP)-2 plays a key role in many biological and pathological processes related to cell migration, invasion, and mitogenesis. MMP-2 is synthesized as a zymogen that is activated through either a conformational change or proteolysis of the propeptide. Several activating enzymes for pro-MMP-2 have been proposed, including metalloproteases and serine proteases. The mechanism of pro-MMP-2 activation by metalloproteases is well established, and the most studied activation mechanism involves cleavage of the propeptide by membrane type 1-MMP (MT1-MMP). In contrast, serine protease activation has not been thoroughly studied, although studies suggest that MT1-MMP may be involved in activation by thrombin and plasmin. Here, we demonstrate that factor Xa mediates MT1-MMP-independent processing of pro-MMP-2 in vascular smooth muscle cells and endothelial cells. Factor Xa and thrombin directly cleaved the propeptide on the carboxyl terminal sides of the Arg 98 and Arg 101 residues, whereas plasmin only cleaved the propeptide downstream of Arg 101 . Moreover, processed MMP-2 showed enzymatic activity that was enhanced by intermolecular autoproteolytic processing at the Asn 109 -Tyr peptide bond. In addition to its role in activation, factor Xa rapidly degraded MMP-2, thereby restricting excessive MMP-2 activity. Thrombin also degraded MMP-2, but the degradation was reduced greatly under cell-associated conditions, resulting in an increase in processed MMP-2. Overall, factor Xa and thrombin regulate MMP-2 enzymatic activity through its activation and degradation. Thus, the net enzymatic activity results from a balance between MMP-2 activation and degradation. Matrix metalloprotease (MMP)3 -2 is a member of the zincdependent endopeptidase family, which comprises 24 enzymes (1). MMP-2 plays a key role in many biological and pathological processes, including organ growth, endometrial cycling, wound healing, bone remodeling, tumor invasion, and metastasis (2). This enzyme functions through proteolysis of non-structural extracellular molecules and components of the basement membrane, including type IV collagen, fibronectin, elastin, laminin, aggrecan, and fibrillin (3).Like most MMPs, MMP-2 is synthesized as a zymogen that is activated by conformational change (4) or proteolysis within the propeptide, which may involve membrane type MMPs (MT-MMPs) (5-9). The most studied activation mechanism for pro-MMP-2 is cleavage of the propeptide by MT1-MMP, which requires cooperative activity between MT1-MMP and tissue inhibitor of metalloprotease (TIMP)-2 (5, 10 -12). Serine proteases, such as thrombin, factor Xa, activated protein C, and plasmin as well as the cysteine protease legumain are all known activators of pro-MMP-2 (13-17). (25,26). Both proteases can also elicit endothelial cell and SMC migration through pro-MMP-2 activation and subsequent extracellular matrix degradation (13,27,28). However, despite studies suggesting that MT1-MMP is involved in thrombin-mediated activation of pro-MMP-2, a detailed mechanism...

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Inactivating Mutation of the Mouse Tissue Inhibitor of Metalloproteinases-2(Timp-2) Gene Alters ProMMP-2 Activation

Cited by 134 publications

References 26 publications

Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2) in prostate cancer tissue

Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2) in prostate cancer tissue

Complex roles of tissue inhibitors of metalloproteinases in cancer

Regulatory Mechanism of Matrix Metalloprotease-2 Enzymatic Activity by Factor Xa and Thrombin

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