• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of molcancBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleMolecular CancerJournal Front Page
Mol Cancer. 2008; 7: 85.
Published online Nov 21, 2008. doi:  10.1186/1476-4598-7-85
PMCID: PMC2599898

Tissue Inhibitor of Metalloproteinases-4. The road less traveled

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) regulate diverse processes, including extracellular matrix (ECM) remodeling, and growth factors and their receptors' activities through the inhibition of matrix metalloproteinases (MMPs). Recent evidence has shown that this family of four members (TIMP-1 to TIMP-4) can also control other important processes, such as proliferation and apoptosis, by a mechanism independent of their MMP inhibitory actions. Of these inhibitors, the most recently identified and least studied is TIMP-4. Initially cloned in human and, later, in mouse, TIMP-4 expression is restricted to heart, kidney, pancreas, colon, testes, brain and adipose tissue. This restricted expression suggests specific and different physiological functions. The present review summarizes the information available for this protein and also provides a putative structural model in order to propose potential relevant directions toward solving its function and role in diseases such as cancer.

Background

The extracellular matrix (ECM) not only maintains the three-dimensional structure of tissues and organs, but also plays critical roles in cell proliferation, differentiation, survival and motility. Key to ECM remodeling are the Matrix Metalloproteases (MMPs) and their inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs) [1]. These proteins constitute a proteolytic system that participates not only in the breakdown of ECM components and subsequent tissue remodeling, but also provides an important regulatory role in the microenvironment [2]. This is accomplished by the ability of MMPs to modulate the availability and activity of growth factors and cytokines or their receptors, and to process adhesion and signaling receptor targets [3]. For these reasons, it is not unexpected that dysregulation of components of this system are common in diverse pathologies. In particular, it has been found that overproduction of MMPs is associated with cancer initiation and progression in diverse tissues [4]. Although there are several mechanisms that regulate MMP expression, the ultimate control is achieved through interaction with the TIMPs. Intuitively, due to their inhibitory actions, members of this family should be able to inhibit cancer invasion and thus, be antitumoral proteins. Nevertheless, under some circumstances, specific MMPs have a dual role in cancer, with antitumoral activities [1]. In addition, recent evidence has shown that members of the TIMP family can also control other important processes such as proliferation and apoptosis by mechanism(s) independent of their MMP inhibitory actions [5]. This family is composed of four members with high sequence homology and structural identity, but with different tissue expression, regulation and inhibitory characteristics. The most recently identified and least studied member of this family is TIMP-4. Initially cloned in human and later in mouse, TIMP-4 expression is restricted to heart, kidney, pancreas, colon, testes, brain and adipose tissue. This restricted expression suggests specific and different physiological functions.

Structure

Human TIMP-4 is a non-glycosylated, 195 amino acids long polypeptide, the largest of the currently identified human inhibitors of matrix metalloproteinases (MMP) (Fig (Fig1).1). TIMP-4 and TIMP-2 are 51% identical at the amino acid level, with TIMP-4 only one residue larger than TIMP-2. Contrastingly, TIMP-4 is eleven and seven residues larger than TIMP-1 and TIMP-3 and shows 37% and 51% identity to these proteins, respectively [6-9] (Table (Table1).1). Distinctive within the TIMP family, TIMP-4 has twelve Cys residues that form six conserved disulfide bridges [8,10]. The three-dimensional (3D) structure of TIMP-4 has not yet been determined, but due to the relative high sequence identity it shares with the other TIMPs, in particular to TIMP-2, a high structural similarity to those proteins could be expected [7]. The TIMPs fold into two very distinct domains, a larger N-terminal domain that carries the MMP inhibitory activity and a smaller C-terminal domain that mediates other non-inhibitory interactions, notably with some pro-MMP forms (Fig (Fig2A)2A) [8,9,11-13]. The N-terminal domain encompasses nearly two-thirds of the polypeptide chain and is reminiscent of the oligonucleotide/oligosaccharide-binding (OB) fold [14-19]. This motif was first described in proteins binding oligonucleotides or oligossacharides [20] and is present in twelve protein superfamilies within the SCOPE (Structural Classification of Proteins, http://scop.mrc-lmb.cam.ac.uk/scop/) data base, including the staphylococcal nucleases, bacterial enterotoxins, heme chaperone CcmE, N-terminal domain of the tail-associated lysozyme gp5 of bacteriophage T4, nucleic acid-binding proteins and inorganic pyrophosphatases, among others [21,22]. The core of the TIMP OB region is formed by a five-stranded anti-parallel β pleated sheet rolled into a β-barrel, stabilized by three disulfide bonds. The strands forming the barrel are connected by loops, which in some cases differ in length from one TIMP to another. Three segments folded in α-helices (α-helix 1 to 3) are associated with the β-barrel core (Fig (Fig2A)2A) [8,12,14-18,23-26]. The N-terminal domain can be expressed and folded independently and, as it was pointed out above, is necessary and sufficient for MMP inhibition [15,27-29].

Table 1
Sequence identity and similarity shown by human and non-human TIMPs compared to the human TIMP-4.
Figure 1
Comparison of the amino acid sequence of the human TIMP-4 (hTIMP-4) with those of the other human TIMPs (hTIMP-1, hTIMP-2, and hTIMP3) and TIMP-4 from Pan troglodytes (paTIMP-4) Mus musculus (muTIMP-4), Rattus norvegicus (raTIMP-4), Bos taurus (boTIMP-4), ...
Figure 2
Cartoon representation of the crystallography structure of the human TIMP-2 in uncomplexed state (A) and the bovine TIMP-2 complexed with the catalytic domain on the metalloproteinase 13 (cdMMP-13) (B). The regions of TIMP-2 folded as helices and β-strands ...

The C-terminal domain folding topology is characterized by a β-hairpin plus a β-loop-β motif with two associated 310-helices (Fig (Fig2)2) [14,16,17,26]. Notably, this fold has not been observed in other proteins different from the TIMPs among the structures deposited at the Brookhaven Protein Data Bank (http://www.rcsb.org/pdb/home/home/.do).

Crystallographic structure analysis of the TIMPs in complex with MMPs has shown that the long edge of the wedged-shaped inhibitor occupies the entire length of the MMP active-site cleft. A central part of this molecular edge is formed by a short stretch of five relatively conserved residues at the N-terminus that adopts an extended conformation and a portion of the loop connecting the β-strands C and D (CD-loop) (Fig (Fig2B).2B). The pentapeptide N-terminal segment is connected to the core of the β-barrel by two disulfide bridges involving Cys1-Cys70 and Cys3-Cys99 in TIMP-1. Continuing along this segment, the chain folds helically (α-helix 1) and then proceeds into the proper β-barrel motif at strand A (Fig (Fig2)2) [14-16,19,23,25]. It has been shown that the residues at the molecular edge critically contribute to defining the specificity and affinity of the inhibitory binding to the MMPs. Mutational analysis of Thr2 in TIMP-1 and Ser2 in TIMP-4 has shown that size, charge and polarity of residue two in the TIMP structure is a major determinant of MMP inhibition [16,23,27,29-32].

From the alignment shown in Fig. Fig.1,1, it is apparent that in TIMP-4 the β-hairpin connecting the β-strands A and B (AB-loop) differs in sequence and length relative to the corresponding region in the other TIMPs. This loop is one residue shorter than in TIMP-2 and six and five residues larger than in TIMP-1 and TIMP-3, respectively. Crystallographic, NMR and site-directed mutagenesis studies have revealed that the AB-loop is variably involved in the contacts between TIMPs and MMPs [14-16,23]. It has been shown that deleting this loop dramatically decreases the rate of association and increases the equilibrium constant of TIMP-2 binding to the catalytic domain of MT1-MMP (MMP-14) [33]. It was demonstrated that Tyr36, which is unique within the TIMP-2 sequence and located at the tip of the AB-loop, critically contributes to the interactions with MT1-MMP [34]. Notably, the deletion of the AB-loop in TIMP-4 exerts a considerably smaller effect in the kinetics and thermodynamic of binding with MT1-MMP, suggesting a different contribution of the TIMP-4 AB-loop for the MT1-MMP binding [33]. TIMP-4, which associates with the catalytic domain of MT1-MMP at a 20-fold slower rate than TIMP-2, has Ala instead of Tyr at position 36. Moreover, TIMP-4 has two Pro residues at positions relevant for the AB-loop that are not present in the other TIMPs. Pro30 is located at the beginning and Pro35 at the tip of the AB loop. In addition, Pro39 distinguishes the AB-loop of TIMP-2 and TIMP-3 but is substituted for Thr in TIMP-4 (Fig (Fig1).1). These characteristics of the TIMP-4 AB-loop sequence, that presumably induce local differences respecting to TIMP-2 AB-loop, could also be of relevance for MT1-MMP binding. Remarkably, it was shown that grafting the entire TIMP-2 AB-loop to TIMP-4 transfers the MT1-MMP binding functionality of TIMP-2 AB-loop to TIMP-4. Improvement in the MT1-MMP-binding capacity was also observed when the three residues located at the tip of the TIMP-2 AB-loop, including Tyr36, were transferred to TIMP-4 (Fig. (Fig.1).1). It is of note that in both cases, Pro30 and Pro35 in TIMP-4 were replaced by the corresponding residues in TIMP-2 [33].

It is known that TIMP-4 binds to pro-MMP-2 as TIMP-2 does and is also a strong inhibitor of MT1-MMP; however, notwithstanding the sequence similarity between both inhibitors, TIMP-4 is unable to promote the activation of the pro-MMP-2 by free MT1-MMP enzyme [35]. This action is uniquely facilitated by TIMP-2 and is proposed to require the formation of a membrane ternary complex that includes TIMP-2, pro-MMP-2 and MT1-MMP [36-38]. The crystallographic study of the complex formed by TIMP-2 and pro-MMP-2 has shown that it involves the interaction of the C-terminal domain of the inhibitor with the hemopexin-like domain of the zymogen [17]. Sequence differences at the C-terminal domain between TIMP-4 and TIMP-2 have been suggested to be the cause of the inability of TIMP-4 to promote the activation of pro-MMP-2. TIMP-4 lacks the Met149, Glu192 and Asp193 residues that have been proposed to be key in stabilizing the interactions of the C-terminal domain of TIMP-2 with the hemopexin-like domain of pro-MMP-2. In TIMP-4, Glu192 and Asp193 are replaced by Val and Gln, respectively. In addition, Met149, around which the main cluster of hydrophobic interactions between TIMP-2 and pro-MMP-2 focuses, is replaced in TIMP-4 by Thr. In support of this suggestion, it was recently demonstrated that, in clear contrast with TIMP-2, TIMP-4 is unable to form in vitro a stable complex with pro-MMP-2 in presence of the active form of MT1-MMP [33].

At present, six non-human TIMP-4 sequences, five of them from mammals, have been reported [39-42] (Fig (Fig1).1). Those of mammalian origin are 90 to 100% identical to hTIMP-4, with the chimpanzee TIMP-4 (paTIMP-4) the most closely related. In contrast, the TIMP-4 of the fish Takifugu rubripes (tkTIMP-4) shows only 55% identity to hTIMP-4 [42], a value that compares with the similarity between hTIMP-2 and hTIMP-4. Interestingly, tkTIMP-4 and hTIMP-2 are 50% identical at the sequence level, which is in agreement with the proposed hypothesis of a relatively close common ancestor for both TIMP-2 and TIMP-4 (Fig (Fig11 and Table Table1)1) [8,42,43].

Regulation

Although the four members of the TIMP family are very similar in structure, they present marked differences in their expression pattern. While TIMP-2 expression is constitutive and ubiquitous, TIMP-1, -3 and -4 expression is inducible and tissue specific. TIMP-1 is mainly expressed in the reproductive system; TIMP-3 in the heart, kidney, and thymus, and TIMP-4 in heart, kidney, pancreas, colon, testes, brain and adipose tissue [7]. TIMP genes have been found in species ranging from Caenorhabditis elegans to humans, suggesting a important and conserved role in metazoans [8]. Interestingly, TIMP-1, 3 and 4 genes are nested within introns of the synapsin gene family [44]. Since synapsins are neuronal-specific phosphoproteins involved in synaptogenesis and neurotransmitter release, it is possible that TIMPs could have a regulatory role in the brain. Characterization of mouse TIMP-4 promoter showed potential sites for myogenin, GATA and Ets family members. Interestingly, it lacks AP1 or AP2 sites, which are involved in the inducible and basal expression of TIMP-1, -2 and -3 genes [45]. Additionally, the TIMP-4 promoter contains an estrogen response element (ERE), in accordance with the observed regulation by estrogen during endometrial normal cycle and preimplantation period [46,47]. Similar to TIMP-3, TIMP-4 expression is regulated by promoter methylation in cancer cell lines and tumor samples [48]. In addition, a polymorphism in the region that transcribes the 3' UTR of the TIMP-4 has been identified. The effect of this polymorphism on TIMP-4 expression and function is unknown, however it is associated with a major risk for osteoarthritis in the Korean population [49]. TIMP-4 function is also regulated by postranslational modifications. Peroxinitrite-induced nitration and oligomerization impairs the inhibitory effects of this protein on MMP-2. In this case, four tyrosine residues on TIMP-4 are modified by peroxynitrite exposure. Since peroxynitrite, via post-translational modifications of target proteins, contributes to cardiovascular injury and cancer, its effect on TIMP-4 could be involved in the pathology of these diseases [50].

Cellular functions

The most widely studied function of TIMPs is their inhibition properties on MMPs. Members of the MMP family include the classical MMPs, the membrane-bound MMPs (MT-MMPs), the ADAMs (a disintegrin and metalloproteinase) and the ADAMTS (a disintegrin and metalloproteinase with thrombospodin motif) [51]. These enzymes and their specific inhibitors are involved in tumor progression and metastasis by regulating extracellular matrix degradation [4]. As mentioned above, TIMP-4 is more closely related to TIMP-2 and -3, than to TIMP-1. Accordingly, the catalytic domain of MMP-19 can be inhibited by TIMP-2, -3 and -4, while TIMP-1 is less efficient [52] (Table (Table2).2). Additionally, MMP-26 is inhibited by the same group of TIMPs, and the co-expression of these proteins has been observed in endometrial carcinoma [53] and in breast ductal carcinoma in situ (DCIS) [54]. Enzymatic kinetics studies revealed IC50 values of 19, 3, 45, 8, 83, and 0.4 nM for MMP-1, MMP-2, MMP-3, MMP-7, MMP-9 and MMP-26, respectively, thus demonstrating that TIMP-4 has highest affinity for MMP-26 among these MMPs [55-57] (Table (Table2).2). A special case is TIMP-2, which is the only member of the family able to both inhibit and activate MMPs. Although TIMP-4 is able to form a complex with MT1-MMP and the hemopexin domain of MMP-2, it cannot activate the metalloproteinase. However, TIMP-4 can regulate the activity of MMP-2 by efficient inhibition of MT1-MMP-mediated activation and by inhibiting the activated enzyme [35,58,59].

Table 2
Inhibitory activity of TIMP-4 on matrix metalloproteinases.

TIMPs can also inhibit members of the ADAM and ADAMTS families. ADAMTSs are structurally and evolutionarily more related to the ADAM family, and more distantly to MMPs [60]. TIMP-4 and -3 can inhibit the proteolytic activity of ADAM28 on insulin-like growth factor binding protein-3 (IGFBP-3) [61]. Protease activity of ADAM33 is also inhibited moderately by TIMP-3 and -4 and weakly inhibited by TIMP-2 but not by TIMP-1 [62]. In contrast, proteolytic activity of ADAM10 on myelin basic protein can be inhibited by TIMP-1 and -3, while TIMP-2 and -4 were unable to inhibit this activity [63]. TIMP-3 is also a good inhibitor of ADAM17, while TIMP-2 and -4 are weak inhibitors, TIMP-1 did not show inhibition [64]. However a TIMP-4 mutant, in which three residues in the AB loop were replaced by surface residues of TIMP-3, showed a ten-fold increase in the binding affinity to ADAM17 [65]. For ADAMTS4, TIMP-3 is the most efficient inhibitor, followed by TIMP-1 and -2, while TIMP-4 is a less efficient inhibitor [66]. ADAMTS2 is only inhibited by TIMP-3, while TIMP-1, -2 and -4 did not show inhibitory activity [67]. Although ADAMTS5 is inhibited by TIMP-3, TIMP-4 is a weak inhibitor and no inhibition by TIMP-1 and -2 was observed [68]. Platelets contain and release several members of the TIMP, MMP and ADAM families, including MMP-1, MMP-2, MMP-3, MMP-9, MT1-MMP (MMP-14), ADAM10, ADAM17, ADAMTS13, TIMP-1, TIMP-2 and TIMP-4. These proteins regulate platelet functions such as agonist-stimulated platelet adhesion and aggregation, tumor cell-induced platelet aggregation and platelet-leukocyte aggregation [69]. TIMP-4 has been identified as the major MMP inhibitor in human platelets [70], so it is possible that this protein has an important regulatory role in these phenomena.

In addition to their inhibitory actions, TIMPs have independent cell signaling functions that modulate angiogenesis, proliferation and apoptosis [71]. Mutants that lack the ability to inhibit MMPs but retain the capacity to modulate specific cellular functions [72] have substantiated the MMP-independent activities of both TIMP-1 and TIMP-2. It has been shown that one of these mutants, Thr2Gly-TIMP1, is able to protect MCF10A human breast epithelial cell from apoptosis as efficiently as the wild type TIMP-1 [71]. Similarly, a TIMP-2 mutant containing an appending Ala residue at the amino terminus (Ala+TIMP-2) binds the surface of human A549 cancer cells with high affinity and retains an in vitro cell growth-inhibitory activity similar to the TIMP-2 wild type protein regardless of being a non-active MMP-inhibitor [73]. Recently, a mayor breakthrough in MMP-independent activities was achieved by the discovery of binding partners for TIMP-1, 2 and 3 as CD63, integrin a3b1 and VEGF receptor-2, respectively, and putatively CD63 for TIMP-4 [74]. Although not firmly established, the TIMP-4 association could imply a similar role to that of TIMP-1, that is, the ability to activate integrin b1 complex and promote survival signaling pathways such as FAK, Src, PI 3-K and MAPK. TIMP-4 mutants that lack MMP-inhibitory activity could be helpful in elucidating the MMP-dependence or independence of normal and cancer cells' behavior [72]. This goal would be greatly facilitated by studies around the structural basis of TIMP-4 MMP-inhibitory specificity. TIMP-4 has proven to be difficult to fold efficiently in vitro from bacterial inclusion bodies but it can be expressed in mammalian cells [35], baculovirus [55], and yeast [32], in a quantity that could facilitate the production of crystals suitable for structural studies. For obvious reasons, determining the 3-D structure of free TIMP-4 as well as in complex with relevant MMPs will be an important forward step. Site-directed mutagenesis studies as well as the construction of chimeras by domain-exchange could be helpful in identifying which region at the N- and/or C- terminal domains of TIMP-4 are involved in binding to the putative cellular receptor.

Role in cancer progression

Tumor microenvironment is key to cancer progression. To survive and to achieve their full malignant phenotype, cancer cells require signaling via adhesion molecules with surrounding non-neoplastic cells, paracrine loops of released signaling factors and extracellular matrix interaction and degradation.

In particular, the extracellular matrix (ECM) presents not only as a structural impediment to neoplastic cells' migration, but also contributes to their behavior by providing biochemical clues such as growth factor and cytokines that are anchored to it. Matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and tissue inhibitors of metalloproteinases (TIMPs) constitute the major proteolytic axis of ECM, and thus, are critical for cancer progression.

For these reasons, it is not unexpected that TIMP-4 is disregulated during cancer progression of several organs. Elevated levels of TIMP-4 have been found in breast, ovary, cervical, prostate, brain, colon, endometrium and papillary renal tumors, whereas down-regulation was observed in pancreatic and clear cell renal tumors (Table (Table3)3) [75-78]. This list is not comprehensive, since an expression profile in the Oncomine database [79], which contains microarray expression data for multiple cancer types, shows that other cancer types also present up-regulated levels of TIMP-4, including oligodendrogliomas and astrocytomas, seminomas and hairy cell leukemias (Table (Table44).

Table 3
TIMP-4 expression in human cancer.
Table 4
TIMP-4 expression in human cancer.

Interestingly, down-regulated levels were found in bladder, prostate and head and neck cancer. Three possible reasons, not mutually exclusive, could explain these opposing results. First, the methods used may account for some of the results. Since it has been shown that there are different TIMP-4 protein pools [80], mRNA expression analyses may not accurately reflect protein levels at a particular time point. Second, disease or tissue-specific differences may account for some of the results. This is exemplified by renal cell carcinoma, in which TIMP-4 is elevated in papillary cancer cells, in contrast with clear cell carcinoma, in which TIMP-4 mRNA is reduced [81]. Finally, temporal expressional changes during cancer progression could also explain the differences. Thus, analysis of samples at later stages may detect only a TIMP-4 decrease, missing early changes, especially when the studies lack samples from initial cancer stages or normal tissue controls. Supporting this scenario, it has been shown that TIMP-4 increases in initial stages of prostate, breast and glial tumors, decreasing at later stages (Table (Table3).3). A decrease in expression at later stages has also been found for pancreatic and endometrial tumors.

Clearly, additional studies using a wider range and number of samples are needed to draw a conclusion, but, for some tumors, a scenario in which TIMP-4 marks the transition to invasive cancer emerges. This transition seems also to be correlated with the expression of MMP-26, a metalloproteinase inhibited by TIMP-4, providing an important invasive proteolytic axis [54]. Since MMP-26 promotes invasion by dissolving basement membrane after activation of MMP-9 [82], TIMP-4 may be acting as a natural anti-invasive protein by preventing activation of MMP-2 and 9, in a direct and indirect manner, as described previously. This coexpression has been clearly demonstrated in prostate [83], breast [54] and endometrial carcinomas [53], with the last two associated with the estrogen receptor signaling pathway. Nevertheless, there are two conflicting results. First, in contrast to early reports on the antitumoral function of TIMP-4 on breast cancer tumor growth and invasion [84], Jiang et al. reported that systemic delivery of TIMP-4 stimulated breast cancer tumorigenesis [85]. Although conclusive for the particular cell line, this last report is not valid, since there is ample evidence that the cell line used, MDA-435, is really a melanoma line [86]. These results urgently call for a new in vivo study. Second, Savinov et al. [87] have shown that MMP-26 up-regulation in breast ductal carcinoma in situ correlates with longer patient survival, perhaps due to the intracellular cleavage of ER-beta by this protease. These authors later propose that the MMP-26 mislocalization may be inhibiting cancer progression by its effects on ER-beta [88]. Since TIMP-4 was not measured, no conclusion regarding TIMP-4 correlation with breast cancer progression can be made, although further studies on the possible dual role of this inhibitor are warranted.

All these results point toward the need to perform additional studies to determinate the relevance of TIMP-4 in cancer invasion and progression, in particular to establish if a positive correlation with prognosis or inverse correlation with invasion in patients can be made. In addition, in light of the problems with previous models, the possible use of TIMP-4 as a therapeutic target should not be dismissed. Finally, it is important to study the potential relevance of the possible new transduction partners of TIMP-4 on cancer progression and to identify the importance of their localization.

Conclusion

Compared to other members of the family, TIMP-4 has received less attention than deserved, perhaps due to the restricted tissue expression and suspected pro-tumoral activities. Nevertheless, the recent reports showing a correlation between its expression and invasion and the problems with the in vivo models warrant additional efforts to establish the relevance of this protein in cancer. In particular, additional studies are needed to elucidate its molecular functions and intracellular role(s), analyze its potential as a biomarker and to test if it could be a therapeutic target. These efforts surely will get TIMP-4 the attention it needs from the scientific community.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

JM-Z coordinated the work, wrote several parts of the article and proofreaded the manuscript, LDP wrote the structure section, GC wrote the regulation section and VM wrote the cancer progression section. All authors read and approved the final manuscript.

References

  • Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8:221–233. doi: 10.1038/nrm2125. [PMC free article] [PubMed] [Cross Ref]
  • Noel A, Jost M, Maquoi E. Matrix metalloproteinases at cancer tumor-host interface. Semin Cell Dev Biol. 2008;19:52–60. doi: 10.1016/j.semcdb.2007.05.011. [PubMed] [Cross Ref]
  • Fu X, Parks WC, Heinecke JW. Activation and silencing of matrix metalloproteinases. Semin Cell Dev Biol. 2008;19:2–13. doi: 10.1016/j.semcdb.2007.06.005. [PubMed] [Cross Ref]
  • Rydlova M, Holubec L, Jr, Ludvikova M, Jr, Kalfert D, Franekova J, Povysil C, Ludvikova M. Biological activity and clinical implications of the matrix metalloproteinases. Anticancer Res. 2008;28:1389–1397. [PubMed]
  • Stetler-Stevenson WG. The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. Cancer Metastasis Rev. 2008;27:57–66. doi: 10.1007/s10555-007-9105-8. [PMC free article] [PubMed] [Cross Ref]
  • Olson TM, Hirohata S, Ye J, Leco K, Seldin MF, Apte SS. Cloning of the human tissue inhibitor of metalloproteinase-4 gene (TIMP4) and localization of the TIMP4 and Timp4 genes to human chromosome 3p25 and mouse chromosome 6, respectively. Genomics. 1998;51:148–151. doi: 10.1006/geno.1998.5362. [PubMed] [Cross Ref]
  • Greene J, Wang M, Liu YE, Raymond LA, Rosen C, Shi YE. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem. 1996;271:30375–30380. doi: 10.1074/jbc.271.48.30375. [PubMed] [Cross Ref]
  • Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta. 2000;1477:1–2. [PubMed]
  • Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997;74:111–122. [PubMed]
  • Denhardt DT, Feng B, Edwards DR, Cocuzzi ET, Malyankar UM. Tissue inhibitor of metalloproteinases (TIMP, aka EPA): structure, control of expression and biological functions. Pharmacol Ther. 1993;59:329–341. doi: 10.1016/0163-7258(93)90074-N. [PubMed] [Cross Ref]
  • Bode W, Fernandez-Catalan C, Grams F, Gomis-Ruth FX, Nagase H, Tschesche H, Maskos K. Insights into MMP-TIMP interactions. Ann N Y Acad Sci. 1999;878:73–91. doi: 10.1111/j.1749-6632.1999.tb07675.x. [PubMed] [Cross Ref]
  • Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–839. doi: 10.1161/01.RES.0000070112.80711.3D. [PubMed] [Cross Ref]
  • Wojtowicz-Praga SM, Dickson RB, Hawkins MJ. Matrix metalloproteinase inhibitors. Invest New Drugs. 1997;15:61–75. doi: 10.1023/A:1005722729132. [PubMed] [Cross Ref]
  • Fernandez-Catalan C, Bode W, Huber R, Turk D, Calvete JJ, Lichte A, Tschesche H, Maskos K. Crystal structure of the complex formed by the membrane type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor. Embo J. 1998;17:5238–5248. doi: 10.1093/emboj/17.17.5238. [PMC free article] [PubMed] [Cross Ref]
  • Iyer S, Wei S, Brew K, Acharya KR. Crystal structure of the catalytic domain of matrix metalloproteinase-1 in complex with the inhibitory domain of tissue inhibitor of metalloproteinase-1. J Biol Chem. 2007;282:364–371. doi: 10.1074/jbc.M607625200. [PubMed] [Cross Ref]
  • Maskos K, Lang R, Tschesche H, Bode W. Flexibility and variability of TIMP binding: X-ray structure of the complex between collagenase-3/MMP-13 and TIMP-2. J Mol Biol. 2007;366:1222–1231. doi: 10.1016/j.jmb.2006.11.072. [PubMed] [Cross Ref]
  • Morgunova E, Tuuttila A, Bergmann U, Tryggvason K. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci USA. 2002;99:7414–7419. doi: 10.1073/pnas.102185399. [PMC free article] [PubMed] [Cross Ref]
  • Muskett FW, Frenkiel TA, Feeney J, Freedman RB, Carr MD, Williamson RA. High resolution structure of the N-terminal domain of tissue inhibitor of metalloproteinases-2 and characterization of its interaction site with matrix metalloproteinase-3. J Biol Chem. 1998;273:21736–21743. doi: 10.1074/jbc.273.34.21736. [PubMed] [Cross Ref]
  • Wu B, Arumugam S, Gao G, Lee GI, Semenchenko V, Huang W, Brew K, Van Doren SR. NMR structure of tissue inhibitor of metalloproteinases-1 implicates localized induced fit in recognition of matrix metalloproteinases. J Mol Biol. 2000;295:257–268. doi: 10.1006/jmbi.1999.3362. [PubMed] [Cross Ref]
  • Murzin AG. OB(oligonucleotide/oligosaccharide binding)-fold: common structural and functional solution for non-homologous sequences. Embo J. 1993;12:861–867. [PMC free article] [PubMed]
  • Arnesano F, Banci L, Barker PD, Bertini I, Rosato A, Su XC, Viezzoli MS. Solution structure and characterization of the heme chaperone CcmE. Biochemistry. 2002;41:13587–13594. doi: 10.1021/bi026362w. [PubMed] [Cross Ref]
  • Kanamaru S, Leiman PG, Kostyuchenko VA, Chipman PR, Mesyanzhinov VV, Arisaka F, Rossmann MG. Structure of the cell-puncturing device of bacteriophage T4. Nature. 2002;415:553–557. doi: 10.1038/415553a. [PubMed] [Cross Ref]
  • Gomis-Ruth FX, Maskos K, Betz M, Bergner A, Huber R, Suzuki K, Yoshida N, Nagase H, Brew K, Bourenkov GP, et al. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature. 1997;389:77–81. doi: 10.1038/37995. [PubMed] [Cross Ref]
  • Maskos K, Bode W. Structural basis of matrix metalloproteinases and tissue inhibitors of metalloproteinases. Mol Biotechnol. 2003;25:241–266. doi: 10.1385/MB:25:3:241. [PubMed] [Cross Ref]
  • Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562–573. doi: 10.1016/j.cardiores.2005.12.002. [PubMed] [Cross Ref]
  • Tuuttila A, Morgunova E, Bergmann U, Lindqvist Y, Maskos K, Fernandez-Catalan C, Bode W, Tryggvason K, Schneider G. Three-dimensional structure of human tissue inhibitor of metalloproteinases-2 at 2.1 A resolution. J Mol Biol. 1998;284:1133–1140. doi: 10.1006/jmbi.1998.2223. [PubMed] [Cross Ref]
  • Huang W, Meng Q, Suzuki K, Nagase H, Brew K. Mutational study of the amino-terminal domain of human tissue inhibitor of metalloproteinases 1 (TIMP-1) locates an inhibitory region for matrix metalloproteinases. J Biol Chem. 1997;272:22086–22091. doi: 10.1074/jbc.272.35.22086. [PubMed] [Cross Ref]
  • Huang W, Suzuki K, Nagase H, Arumugam S, Van Doren SR, Brew K. Folding and characterization of the amino-terminal domain of human tissue inhibitor of metalloproteinases-1 (TIMP-1) expressed at high yield in E. coli. FEBS Lett. 1996;384:155–161. doi: 10.1016/0014-5793(96)00304-3. [PubMed] [Cross Ref]
  • Lee MH, Verma V, Maskos K, Nath D, Knauper V, Dodds P, Amour A, Murphy G. Engineering N-terminal domain of tissue inhibitor of metalloproteinase (TIMP)-3 to be a better inhibitor against tumour necrosis factor-alpha-converting enzyme. Biochem J. 2002;364:227–234. [PMC free article] [PubMed]
  • Hamze AB, Wei S, Bahudhanapati H, Kota S, Acharya KR, Brew K. Constraining specificity in the N-domain of tissue inhibitor of metalloproteinases-1; gelatinase-selective inhibitors. Protein Sci. 2007;16:1905–1913. doi: 10.1110/ps.072978507. [PMC free article] [PubMed] [Cross Ref]
  • Meng Q, Malinovskii V, Huang W, Hu Y, Chung L, Nagase H, Bode W, Maskos K, Brew K. Residue 2 of TIMP-1 is a major determinant of affinity and specificity for matrix metalloproteinases but effects of substitutions do not correlate with those of the corresponding P1' residue of substrate. J Biol Chem. 1999;274:10184–10189. doi: 10.1074/jbc.274.15.10184. [PubMed] [Cross Ref]
  • Stratmann B, Farr M, Tschesche H. MMP-TIMP interaction depends on residue 2 in TIMP-4. FEBS Lett. 2001;507:285–287. doi: 10.1016/S0014-5793(01)02987-8. [PubMed] [Cross Ref]
  • Rapti M, Knauper V, Murphy G, Williamson RA. Characterization of the AB loop region of TIMP-2. Involvement in pro-MMP-2 activation. J Biol Chem. 2006;281:23386–23394. doi: 10.1074/jbc.M604423200. [PubMed] [Cross Ref]
  • Williamson RA, Hutton M, Vogt G, Rapti M, Knauper V, Carr MD, Murphy G. Tyrosine 36 plays a critical role in the interaction of the AB loop of tissue inhibitor of metalloproteinases-2 with matrix metalloproteinase-14. J Biol Chem. 2001;276:32966–32970. doi: 10.1074/jbc.M101843200. [PubMed] [Cross Ref]
  • Bigg HF, Morrison CJ, Butler GS, Bogoyevitch MA, Wang Z, Soloway PD, Overall CM. Tissue inhibitor of metalloproteinases-4 inhibits but does not support the activation of gelatinase A via efficient inhibition of membrane type 1-matrix metalloproteinase. Cancer Res. 2001;61:3610–3618. [PubMed]
  • Overall CM, Tam E, McQuibban GA, Morrison C, Wallon UM, Bigg HF, King AE, Roberts CR. Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation. J Biol Chem. 2000;275:39497–39506. doi: 10.1074/jbc.M005932200. [PubMed] [Cross Ref]
  • Murphy G, Stanton H, Cowell S, Butler G, Knauper V, Atkinson S, Gavrilovic J. Mechanisms for pro matrix metalloproteinase activation. Apmis. 1999;107:38–44. [PubMed]
  • Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, Schade van Westrum S, Crabbe T, Clements J, d'Ortho MP, Murphy G. The TIMP2 membrane type 1 metalloproteinase "receptor" regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem. 1998;273:871–880. doi: 10.1074/jbc.273.2.871. [PubMed] [Cross Ref]
  • Rahkonen OP, Koskivirta IM, Oksjoki SM, Jokinen E, Vuorio EI. Characterization of the murine Timp4 gene, localization within intron 5 of the synapsin 2 gene and tissue distribution of the mRNA. Biochim Biophys Acta. 2002;1577:45–52. [PubMed]
  • Lalu MM, Cena J, Chowdhury R, Lam A, Schulz R. Matrix metalloproteinases contribute to endotoxin and interleukin-1beta induced vascular dysfunction. Br J Pharmacol. 2006;149:31–42. doi: 10.1038/sj.bjp.0706823. [PMC free article] [PubMed] [Cross Ref]
  • Reno C, Boykiw R, Martinez ML, Hart DA. Temporal alterations in mRNA levels for proteinases and inhibitors and their potential regulators in the healing medial collateral ligament. Biochem Biophys Res Commun. 1998;252:757–763. doi: 10.1006/bbrc.1998.9734. [PubMed] [Cross Ref]
  • Yu WP, Brenner S, Venkatesh B. Duplication, degeneration and subfunctionalization of the nested synapsin-Timp genes in Fugu. Trends Genet. 2003;19:180–183. doi: 10.1016/S0168-9525(03)00048-9. [PubMed] [Cross Ref]
  • Kubota S, Kinoshita M, Uji S, Yokoyama Y, Yamamoto E, Hirono I, Aoki T, Sakaguchi M, Morioka K, Itoh Y, et al. Occurrence of two distinct types of tissue inhibitor of metalloproteinases-2 in teleost fish. Biochim Biophys Acta. 2003;1629:102–108. [PubMed]
  • Derry JM, Barnard PJ. Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes. Genomics. 1992;12:632–638. doi: 10.1016/0888-7543(92)90286-2. [PubMed] [Cross Ref]
  • Young DA, Phillips BW, Lundy C, Nuttall RK, Hogan A, Schultz GA, Leco KJ, Clark IM, Edwards DR. Identification of an initiator-like element essential for the expression of the tissue inhibitor of metalloproteinases-4 (Timp-4) gene. Biochem J. 2002;364:89–99. [PMC free article] [PubMed]
  • Pilka R, Domanski H, Hansson S, Eriksson P, Casslen B. Endometrial TIMP-4 mRNA is high at midcycle and in hyperplasia, but down-regulated in malignant tumours. Coordinated expression with MMP-26. Mol Hum Reprod. 2004;10:641–650. doi: 10.1093/molehr/gah092. [PubMed] [Cross Ref]
  • Pilka R, Oborna I, Lichnovsky V, Havelka P, Fingerova H, Eriksson P, Hansson S, Casslen B. Endometrial expression of the estrogen-sensitive genes MMP-26 and TIMP-4 is altered by a substitution protocol without down-regulation in IVF patients. Hum Reprod. 2006;21:3146–3156. doi: 10.1093/humrep/del180. [PubMed] [Cross Ref]
  • Dammann R, Strunnikova M, Schagdarsurengin U, Rastetter M, Papritz M, Hattenhorst UE, Hofmann HS, Silber RE, Burdach S, Hansen G. CpG island methylation and expression of tumour-associated genes in lung carcinoma. Eur J Cancer. 2005;41:1223–1236. doi: 10.1016/j.ejca.2005.02.020. [PubMed] [Cross Ref]
  • Lee HJ, Lee GH, Nah S, Lee KH, Yang H, Kim YM, Chun W, Hong S, Kim S. Association of TIMP-4 gene polymorphism with the risk of osteoarthritis in the Korean population. Rheumatol Int. 2008;28:845–850. doi: 10.1007/s00296-008-0545-4. [PubMed] [Cross Ref]
  • Donnini S, Monti M, Roncone R, Morbidelli L, Rocchigiani M, Oliviero S, Casella L, Giachetti A, Schulz R, Ziche M. Peroxynitrite inactivates human-tissue inhibitor of metalloproteinase-4. FEBS Lett. 2008;582:1135–1140. doi: 10.1016/j.febslet.2008.02.080. [PubMed] [Cross Ref]
  • Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci. 2006;11:1696–1701. doi: 10.2741/1915. [PubMed] [Cross Ref]
  • Stracke JO, Hutton M, Stewart M, Pendas AM, Smith B, Lopez-Otin C, Murphy G, Knauper V. Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme. J Biol Chem. 2000;275:14809–14816. doi: 10.1074/jbc.275.20.14809. [PubMed] [Cross Ref]
  • Tunuguntla R, Ripley D, Sang QX, Chegini N. Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinases TIMP-3 and -4 in benign endometrium and endometrial cancer. Gynecol Oncol. 2003;89:453–459. doi: 10.1016/S0090-8258(03)00077-5. [PubMed] [Cross Ref]
  • Zhao YG, Xiao AZ, Park HI, Newcomer RG, Yan M, Man YG, Heffelfinger SC, Sang QX. Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and -4: a putative role in the initiation of breast cancer invasion. Cancer Res. 2004;64:590–598. doi: 10.1158/0008-5472.CAN-03-1932. [PubMed] [Cross Ref]
  • Liu YE, Wang M, Greene J, Su J, Ullrich S, Li H, Sheng S, Alexander P, Sang QA, Shi YE. Preparation and characterization of recombinant tissue inhibitor of metalloproteinase 4 (TIMP-4) J Biol Chem. 1997;272:20479–20483. doi: 10.1074/jbc.272.33.20479. [PubMed] [Cross Ref]
  • Zhang J, Cao YJ, Zhao YG, Sang QX, Duan EK. Expression of matrix metalloproteinase-26 and tissue inhibitor of metalloproteinase-4 in human normal cytotrophoblast cells and a choriocarcinoma cell line, JEG-3. Mol Hum Reprod. 2002;8:659–666. doi: 10.1093/molehr/8.7.659. [PubMed] [Cross Ref]
  • Troeberg L, Tanaka M, Wait R, Shi YE, Brew K, Nagase H. E. coli expression of TIMP-4 and comparative kinetic studies with TIMP-1 and TIMP-2: insights into the interactions of TIMPs and matrix metalloproteinase 2 (gelatinase A) Biochemistry. 2002;41:15025–15035. doi: 10.1021/bi026454l. [PubMed] [Cross Ref]
  • Hernandez-Barrantes S, Shimura Y, Soloway PD, Sang QA, Fridman R. Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP. Biochem Biophys Res Commun. 2001;281:126–130. doi: 10.1006/bbrc.2001.4323. [PubMed] [Cross Ref]
  • English JL, Kassiri Z, Koskivirta I, Atkinson SJ, Di Grappa M, Soloway PD, Nagase H, Vuorio E, Murphy G, Khokha R. Individual Timp deficiencies differentially impact pro-MMP-2 activation. J Biol Chem. 2006;281:10337–10346. doi: 10.1074/jbc.M512009200. [PubMed] [Cross Ref]
  • Jones GC, Riley GP. ADAMTS proteinases: a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis. Arthritis Res Ther. 2005;7:160–169. doi: 10.1186/ar1783. [PMC free article] [PubMed] [Cross Ref]
  • Mochizuki S, Shimoda M, Shiomi T, Fujii Y, Okada Y. ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein-3. Biochem Biophys Res Commun. 2004;315:79–84. doi: 10.1016/j.bbrc.2004.01.022. [PubMed] [Cross Ref]
  • Zou J, Zhu F, Liu J, Wang W, Zhang R, Garlisi CG, Liu YH, Wang S, Shah H, Wan Y, et al. Catalytic activity of human ADAM33. J Biol Chem. 2004;279:9818–9830. doi: 10.1074/jbc.M309696200. [PubMed] [Cross Ref]
  • Amour A, Knight CG, Webster A, Slocombe PM, Stephens PE, Knauper V, Docherty AJ, Murphy G. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett. 2000;473:275–279. doi: 10.1016/S0014-5793(00)01528-3. [PubMed] [Cross Ref]
  • Amour A, Slocombe PM, Webster A, Butler M, Knight CG, Smith BJ, Stephens PE, Shelley C, Hutton M, Knauper V, et al. TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett. 1998;435:39–44. doi: 10.1016/S0014-5793(98)01031-X. [PubMed] [Cross Ref]
  • Lee MH, Rapti M, Murphy G. Total conversion of tissue inhibitor of metalloproteinase (TIMP) for specific metalloproteinase targeting: fine-tuning TIMP-4 for optimal inhibition of tumor necrosis factor-{alpha}-converting enzyme. J Biol Chem. 2005;280:15967–15975. doi: 10.1074/jbc.M500897200. [PubMed] [Cross Ref]
  • Hashimoto G, Aoki T, Nakamura H, Tanzawa K, Okada Y. Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1, 2, 3 and 4) FEBS Lett. 2001;494:192–195. doi: 10.1016/S0014-5793(01)02323-7. [PubMed] [Cross Ref]
  • Wang WM, Ge G, Lim NH, Nagase H, Greenspan DS. TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2. Biochem J. 2006;398:515–519. doi: 10.1042/BJ20060630. [PMC free article] [PubMed] [Cross Ref]
  • Kashiwagi M, Tortorella M, Nagase H, Brew K. TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5) J Biol Chem. 2001;276:12501–12504. doi: 10.1074/jbc.C000848200. [PubMed] [Cross Ref]
  • Santos-Martinez MJ, Medina C, Jurasz P, Radomski MW. Role of metalloproteinases in platelet function. Thromb Res. 2008;121:535–542. doi: 10.1016/j.thromres.2007.06.002. [PubMed] [Cross Ref]
  • Radomski A, Jurasz P, Sanders EJ, Overall CM, Bigg HF, Edwards DR, Radomski MW. Identification, regulation and role of tissue inhibitor of metalloproteinases-4 (TIMP-4) in human platelets. Br J Pharmacol. 2002;137:1330–1338. doi: 10.1038/sj.bjp.0704936. [PMC free article] [PubMed] [Cross Ref]
  • Chirco R, Liu XW, Jung KK, Kim HR. Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev. 2006;25:99–113. doi: 10.1007/s10555-006-7893-x. [PubMed] [Cross Ref]
  • Stetler-Stevenson WG. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal. 2008;1:re6. doi: 10.1126/scisignal.127re6. [PMC free article] [PubMed] [Cross Ref]
  • Hoegy SE, Oh HR, Corcoran ML, Stetler-Stevenson WG. Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKR-growth factor signaling independent of metalloproteinase inhibition. J Biol Chem. 2001;276:3203–3214. doi: 10.1074/jbc.M008157200. [PubMed] [Cross Ref]
  • Jung KK, Liu XW, Chirco R, Fridman R, Kim HR. Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. Embo J. 2006;25:3934–3942. doi: 10.1038/sj.emboj.7601281. [PMC free article] [PubMed] [Cross Ref]
  • Bister V, Skoog T, Virolainen S, Kiviluoto T, Puolakkainen P, Saarialho-Kere U. Increased expression of matrix metalloproteinases-21 and -26 and TIMP-4 in pancreatic adenocarcinoma. Mod Pathol. 2007;20:1128–1140. doi: 10.1038/modpathol.3800956. [PubMed] [Cross Ref]
  • Groft LL, Muzik H, Rewcastle NB, Johnston RN, Knauper V, Lafleur MA, Forsyth PA, Edwards DR. Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas. Br J Cancer. 2001;85:55–63. doi: 10.1054/bjoc.2001.1854. [PMC free article] [PubMed] [Cross Ref]
  • Lizarraga F, Espinosa M, Maldonado V, Melendez-Zajgla J. Tissue inhibitor of metalloproteinases-4 is expressed in cervical cancer patients. Anticancer Res. 2005;25:623–627. [PubMed]
  • Ripley D, Tunuguntla R, Susi L, Chegini N. Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinase-3 and -4 in normal ovary and ovarian carcinoma. Int J Gynecol Cancer. 2006;16:1794–1800. doi: 10.1111/j.1525-1438.2006.00714.x. [PubMed] [Cross Ref]
  • Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6:1–6. [PMC free article] [PubMed]
  • Hilska M, Roberts PJ, Collan YU, Laine VJ, Kossi J, Hirsimaki P, Rahkonen O, Laato M. Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer. Int J Cancer. 2007;121:714–723. doi: 10.1002/ijc.22747. [PubMed] [Cross Ref]
  • Hagemann T, Gunawan B, Schulz M, Fuzesi L, Binder C. mRNA expression of matrix metalloproteases and their inhibitors differs in subtypes of renal cell carcinomas. Eur J Cancer. 2001;37:1839–1846. doi: 10.1016/S0959-8049(01)00215-5. [PubMed] [Cross Ref]
  • Zhao YG, Xiao AZ, Newcomer RG, Park HI, Kang T, Chung LW, Swanson MG, Zhau HE, Kurhanewicz J, Sang QX. Activation of pro-gelatinase B by endometase/matrilysin-2 promotes invasion of human prostate cancer cells. J Biol Chem. 2003;278:15056–15064. doi: 10.1074/jbc.M210975200. [PubMed] [Cross Ref]
  • Lee S, Desai KK, Iczkowski KA, Newcomer RG, Wu KJ, Zhao YG, Tan WW, Roycik MD, Sang QX. Coordinated peak expression of MMP-26 and TIMP-4 in preinvasive human prostate tumor. Cell Res. 2006;16:750–758. doi: 10.1038/sj.cr.7310089. [PubMed] [Cross Ref]
  • Wang M, Liu YE, Greene J, Sheng S, Fuchs A, Rosen EM, Shi YE. Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene. 1997;14:2767–2774. doi: 10.1038/sj.onc.1201245. [PubMed] [Cross Ref]
  • Jiang Y, Wang M, Celiker MY, Liu YE, Sang QX, Goldberg ID, Shi YE. Stimulation of mammary tumorigenesis by systemic tissue inhibitor of matrix metalloproteinase 4 gene delivery. Cancer Res. 2001;61:2365–2370. [PubMed]
  • Ellison G, Klinowska T, Westwood RF, Docter E, French T, Fox JC. Further evidence to support the melanocytic origin of MDA-MB-435. Mol Pathol. 2002;55:294–299. doi: 10.1136/mp.55.5.294. [PMC free article] [PubMed] [Cross Ref]
  • Savinov AY, Remacle AG, Golubkov VS, Krajewska M, Kennedy S, Duffy MJ, Rozanov DV, Krajewski S, Strongin AY. Matrix metalloproteinase 26 proteolysis of the NH2-terminal domain of the estrogen receptor beta correlates with the survival of breast cancer patients. Cancer Res. 2006;66:2716–2724. doi: 10.1158/0008-5472.CAN-05-3592. [PubMed] [Cross Ref]
  • Strongin AY. Mislocalization and unconventional functions of cellular MMPs in cancer. Cancer Metastasis Rev. 2006;25:87–98. doi: 10.1007/s10555-006-7892-y. [PubMed] [Cross Ref]

Articles from Molecular Cancer are provided here courtesy of BioMed Central
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...