Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis: the specificity is in the detail

2003 ◽  
Vol 70 ◽  
pp. 65-80 ◽  
Author(s):  
Gillian Murphy ◽  
Vera Knäuper ◽  
Meng-Huee Lee ◽  
Augustin Amour ◽  
Joanna R. Worley ◽  
...  
Keyword(s):  
Cell Surface ◽  
Specific Binding ◽  
Heparan Sulphate ◽  
Structural Features ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Inhibitors ◽  
The Matrix ◽  
Membrane Type ◽  
Factor Α ◽  
Pericellular Proteolysis

Pericellular proteolysis represents one of the key modes by which the cell can modulate its environment, involving not only turnover of the extracellular matrix but also the regulation of cell membrane proteins, such as growth factors and their receptors. The metzincins are active players in such proteolytic events, and their mode of regulation is therefore of particular interest and importance. The TIMPs (tissue inhibitors of metalloproteinases) are established endogenous inhibitors of the matrix metalloproteinases (MMPs), and some have intriguing abilities to associate with the pericellular environment. It has been shown that TIMP-2 can bind to cell surface MT1-MMP (membrane-type 1 MMP) to act as a 'receptor' for proMMP-2 (progelatinase A), such that the latter can be activated efficiently in a localized fashion. We have examined the key structural features of TIMP-2 that determine this unique function, showing that Tyr\36 and Glu192-Asp193 are vital for specific interactions with MT1-MMP and proMMP-2 respectively, and hence activation of proMMP-2. TIMP-3 is sequestered at the cell surface by association with the glycosaminoglycan chains of proteoglycans, especially heparan sulphate, and we have shown that it may play a role in the regulation of some ADAMs (a disintegrin and metalloproteinases), including tumour necrosis factor α-converting enzyme (TACE; ADAM17). We have established that key residues in TIMP-3 determine its interaction with TACE. Further studies of the features of TIMP-3 that determine specific binding to both ADAM and glycosaminoglycan are required in order to understand these unique properties.

scholarly journals The Cysteine-rich Domain of the Secreted Proprotein Convertases PC5A and PACE4 Functions as a Cell Surface Anchor and Interacts with Tissue Inhibitors of Metalloproteinases

2005 ◽  
Vol 16 (11) ◽  
pp. 5215-5226 ◽  
Author(s):  
Nadia Nour ◽  
Gaétan Mayer ◽  
John S. Mort ◽  
Alexandre Salvas ◽  
Majambu Mbikay ◽  
...  
Keyword(s):  
Cell Surface ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Endothelial Lipase ◽  
Proprotein Convertases ◽  
Tissue Inhibitors ◽  
Rich Domain ◽  
Liver Sinusoids ◽  
A Cell ◽  
Biochemical Analyses ◽  
Cysteine Rich Domain

The proprotein convertases PC5, PACE4 and furin contain a C-terminal cysteine-rich domain (CRD) of unknown function. We demonstrate that the CRD confers to PC5A and PACE4 properties to bind tissue inhibitors of metalloproteinases (TIMPs) and the cell surface. Confocal microscopy and biochemical analyses revealed that the CRD is essential for cell surface tethering of PC5A and PACE4 and that it colocalizes and coimmunoprecipitates with the full-length and C-terminal domain of TIMP-2. Surface-bound PC5A in TIMP-2 null fibroblasts was only observed upon coexpression with TIMP-2. In COS-1 cells, plasma membrane-associated PC5A can be displaced by heparin, suramin, or heparinases I and III and by competition with excess exogenous TIMP-2. Furthermore, PC5A and TIMP-2 are shown to be colocalized over the surface of enterocytes in the mouse duodenum and jejunum, as well as in liver sinusoids. In conclusion, the CRD of PC5A and PACE4 functions as a cell surface anchor favoring the processing of their cognate surface-anchored substrates, including endothelial lipase.

scholarly journals The Unwounded Skin Remodeling in Animal Models of Diabetes Types 1 and 2

2013 ◽  
pp. 519-526 ◽  
Author(s):  
M. KNAŚ ◽  
M. NICZYPORUK ◽  
A. ZALEWSKA ◽  
H. CAR
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinases ◽  
Diabetes Type ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Control Group ◽  
Diabetes Type 1 ◽  
Tissue Inhibitors ◽  
The Matrix

Diabetes mellitus types 1 and 2 are chronic diseases that cause serious health complications, including dermatologic problems. The diabetic skin is characterized by disturbances in collagen metabolism. A tissue remodeling depends on the degradation of extracellular matrix through the matrix metalloproteinases, which are regulated by e.g. the tissue inhibitors of metalloproteinases. The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) is essential to maintain homeostasis in the skin. The aim of this study was to determine the concentration of metalloproteinase 2, tissue inhibitor of metalloproteinase 3 and the concentration of collagen type 1 in unwounded skin of diabetes type 1 and 2 and healthy controls. The treatment of diabetes resulted in a significant decrease of MMP2, increase of TIMP3 and COL1 concentrations in the skin as compared to the untreated diabetic skin. The concentrations of MMP2 in the skin of treated rats did not show significant differences from the healthy control group. TIMP3 concentrations in the skin of treated rats are not returned to the level observed in the control group. Disturbances of the extracellular matrix of the skin are similar in diabetes type 1 and 2. Application of insulin in diabetes therapy more preferably affects the extracellular matrix homeostasis of the skin.

Tissue Inhibitors of Metalloproteinases (TIMPs): Their Biological Functions and Involvement in Oral Disease

2006 ◽  
Vol 85 (12) ◽  
pp. 1074-1084 ◽  
Author(s):  
J. Verstappen ◽  
J.W. Von den Hoff
Keyword(s):  
Rheumatoid Arthritis ◽  
Oral Disease ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Biological Functions ◽  
Tissue Inhibitors ◽  
Oral Cancers ◽  
Ecm Proteins ◽  
Neck Area ◽  
The Matrix

Several families of enzymes are responsible for the degradation of extracellular matrix (ECM) proteins during the remodeling of tissues. An important family of such enzymes is that of the matrix metalloproteinases (MMPs). To control MMP-mediated ECM breakdown, tissue inhibitors of metalloproteinases (TIMPs) are able to inhibit MMP activity. A disturbed balance of MMPs and TIMPs is found in various pathologic conditions, such as cancer, rheumatoid arthritis, and periodontitis. The role of MMPs in pathology has been extensively described in the literature. The main focus of this review lies in the biological functions of TIMPs and their occurrence in disease, especially in the head and neck area. Their biological functions and their role in diseases like oral cancers and periodontitis, and in the development of cleft palate, will be discussed. Finally, the diagnostic and therapeutical opportunities of TIMPs will be evaluated.

scholarly journals MMP-10, MMP-7, TIMP-1 and TIMP-2 mRNA expression in esophageal cancer

2017 ◽  
Vol 64 (2) ◽  
Author(s):  
Agnieszka Juchniewicz ◽  
Oksana Kowalczuk ◽  
Robert Milewski ◽  
Wojciech Laudański ◽  
Piotr Dzięgielewski ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Matrix Metalloproteinases ◽  
Mrna Expression ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Clinicopathologic Features ◽  
Tumour Stage ◽  
Rt Pcr ◽  
Tissue Inhibitors ◽  
Node Metastasis ◽  
The Matrix

Introduction: Tissue inhibitors of metalloproteinases (TIMP) and the matrix metalloproteinases (MMP) are involved in the spread of cancer. Methods: We have evaluated the matrix metalloproteinases’ (MMP-10, MMP-7) and their inhibitors’ (tissue inhibitors of metalloproteinases – TIMP-1, TIMP-2) mRNA expression in 61 esophageal cancer samples from patients who had undergone surgery, by using real-time quantitative RT-PCR, and correlated the results with the patient clinicopathologic features. Results: MMP-10, MMP-7, TIMP-1, TIMP-2 were overexpressed in 73%, 85%, 55% and 42% of esophageal cancer samples, respectively. The expression of MMP-10, TIMP-1, and TIMP-2 correlated with the tumor size. The MMP-7 overexpression was associated with the tumour stage (I, II vs III, p=0.05) and lymph node metastasis (N0 vs N1, p=0.037). Conclusions: We conclude that in the resected esophageal cancer an increased mRNA expression of MMP-7, MMP-10 and TIMP-1 correlated with clinicopathologic features. We suggest that these genes may play a role during progression of the disease.

Structural features of the reprolysin atrolysin C and tissue inhibitors of metalloproteinases (TIMPs) interaction

2006 ◽  
Vol 347 (3) ◽  
pp. 641-648 ◽  
Author(s):  
Antônio F.M. Pinto ◽  
Renata M.S. Terra ◽  
Jorge A. Guimarães ◽  
Masahide Kashiwagi ◽  
Hideaki Nagase ◽  
...  
Keyword(s):  
Structural Features ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Inhibitors

scholarly journals Localization and temporal regulation of tissue inhibitors of metalloproteinases 3 and 4 in bovine preovulatory follicles

Reproduction ◽  
2004 ◽  
Vol 128 (5) ◽  
pp. 555-564 ◽  
Author(s):  
Qinglei Li ◽  
Leanne J Bakke ◽  
J Richard Pursley ◽  
George W Smith
Keyword(s):  
Extracellular Matrix ◽  
Immunohistochemical Localization ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Matrix Remodeling ◽  
Tissue Inhibitors ◽  
Temporal Regulation ◽  
Thecal Cells ◽  
Preovulatory Follicles ◽  
The Matrix ◽  
Gonadotropin Surge

The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are potential regulators of the focalized extracellular matrix degradation required for ovulation. The objectives of the present study were to determine localization and temporal regulation of TIMP-3 and TIMP-4 mRNA and protein in bovine preovulatory follicles. Ovaries containing preovulatory follicles were collected at 0, 12 and 20 h after GnRH injection for real-time PCR quantification of TIMP-3 and TIMP-4 mRNAs and immunohistochemical localization studies. Additional samples collected at 0, 6, 12, 18 and 24 h post GnRH injection were subjected to Western analysis to determine temporal changes in TIMP-3 and TIMP-4 proteins in the apex and base of preovulatory follicles. Results indicate the gonadotropin surge regulates TIMP-3 and TIMP-4 expression. TIMP-3 and TIMP-4 mRNAs increased within 12 h after GnRH injection. TIMP-3 protein was localized to granulosal and thecal layers of preovulatory follicles and adjacent ovarian stroma, whereas TIMP-4 immunoreactivity was localized to granulosal and thecal cells and ovarian blood vessels. Amounts of TIMP-3 and TIMP-4 proteins in the follicular apex peaked within 12 h post GnRH injection and subsequently declined by 24 h. However, amounts of TIMP-3 and TIMP-4 proteins in the base were not elevated after GnRH administration. Results demonstrate that mRNA and protein for both TIMP-3 and TIMP-4 are increased in bovine preovulatory follicles following the gonadotropin surge. Coordinate expression of TIMPs and MMPs may help regulate the extracellular matrix remodeling characteristic of the ovulatory process.

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