Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration

Sadowski, Thorsten; Dietrich, Sebastian; Koschinsky, F.; Ludwig, Andreas; Proksch, E.; Titz, Bjoern; Sedláček, Radislav

doi:10.1007/s00018-005-4478-8

Cited by 73 publications

(63 citation statements)

References 44 publications

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“…42 MMP-19 was widely expressed by keratinocytes at the basal epidermal layer of keratoacanthomas and sporadically in 40% of the SCCs. We and others have previously reported that MMP-19 is absent from invasive cancer cell nests of well-differentiated SCC, 14,34 and our new findings support these results. Thus, the loss of MMP-19 from basal epithelial cells of keratoacanthomas might serve as a warning sign of cancer development.…”

Section: Discussionsupporting

confidence: 91%

“…Furthermore, in an epithelial carcinogenesis model of HPV16/MMP-9À/À mice, MMP-7 and MMP-13 are only seen in frank carcinoma 33 and in tumors both have been detected exclusively in malignantly transformed squamous cell carcinoma cells but not in premalignant lesions. 34 MMP-7 contributes to the initiation of epithelial-to-mesenchymal transition by cleavage of E-cadherin. 33,35 In keratoacanthomas, MMP-7 protein was not generally expressed in keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Cytoplasmic laminin-5g2 chain serves as a marker of normal migrating wound keratinocytes and is a good indicator of migrating cancer cells in various tumor types as well. 18,34 Several MMPs are known to process laminin-5g2 in vitro. 44 We have previously shown that in cutaneous SCCs, laminin5g2 is widely distributed along the invasive tumor front 26,41 and thus our current data show that, in general, staining for laminin-5 cannot help in differentiation between keratoacanthoma and SCC.…”

Section: Discussionmentioning

confidence: 99%

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Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

et al. 2006

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Keratoacanthomas are rapidly growing hyperproliferative skin tumors that may clinically or histologically be difficult to distinguish from well-differentiated squamous cell cancers (SCCs). UV light, trauma, and immune suppression represent their etiological factors. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated the expression profile of several cancer-related MMPs to find markers that would differentiate keratoacanthomas from SCCs and shed light to the pathobiology of keratoacanthoma. Samples from 31 keratoacanthomas and 15 grade I SCCs were studied using immunohistochemistry for MMP-2, -7, -8, -9, -10, -13, and -19 and p16 and laminin-5c2 chain. In situ hybridization for MMP-7, -10, and -13 was performed in a subset of tumors. Keratinocytes with atypia, presence of neovascularization, and composition of the inflammatory infiltrate were graded from hematoxylin-eosin stainings. MMP-7 was present in the epithelium of 4/31 keratoacanthomas and 9/15 SCCs, MMP-8 in 3/30 keratoacanthomas and 0/15 SCCs, but MMP-13 in 16/31 keratoacanthomas and 10/15 SCCs, and MMP-10 in 28/31 keratoacanthomas and all cancers. MMP-9 was detected in the epithelium in 5/31 keratoacanthomas and 8/15 SCCs, whereas MMP-2 was only present in fibroblasts in both tumors. MMP-19 was upregulated in proliferating epithelium of keratoacanthomas as was p16. Cytoplasmic laminin-5c2 was particularly abundant in keratinocytes at the pushing border of MMP-13-positive keratoacanthomas. We conclude that although some MMPs (MMP-10 and -13) are abundantly expressed in keratoacanthomas, the presence of MMP-7 and -9 in their epithelial pushing border is rare and should raise suspicion of SCC. Further, the loss of MMP-19 and p16 could aid in making the differential diagnosis between well-differentiated SCC and keratoacanthoma. Frequent expression of the transformationspecific MMP-13 in keratoacanthomas suggests that they are not benign tumors but incomplete SCCs.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

et al. 2006

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“…6 The catalytic domain of MMP19 degrades various ECM components including collagen type IV, nidogen-1, fibronectin, tenascin-C isoform, aggrecan, and laminin-5-gamma-2-chain. [7][8][9] The catalytic domain contains the typical zinc-binding motif; the zinc and calcium ions additional to this domain are necessary for structure stability and enzymatic activities of MMPs. 10 The glutamate residue at the zinc binding motif activates the zinc-bound water molecule to provide the nucleophile during cleaving activities on peptide bonds.…”

mentioning

confidence: 99%

Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Chan

Lung

et al. 2011

Intl Journal of Cancer

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The association of Matrix metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelial cells of the nasopharynx. This cancer has a unique racial and geographic distribution with a high incidence in Southern China and Southeast Asia among the Southern Chinese population. 1 The etiology of NPC is believed to be multifactorial including dietary and

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“…Furthermore, the 80-kDa ␥2x form has been associated with tissues undergoing remodeling, whereas full-length ␥2 is found in quiescent tissues (13)(14)(15)(16). Other MMPs, including MMP-3, -12, -13, -14, -19, and -20, have also been shown to cleave the ␥2 chain, generating the ␥2x fragment, inducing epithelial cell migration (15,17,18). In addition to this cleavage site near the coiled-coil region, MMP-14 cleaves the short arm of the ␥2 chain at an additional site (15,19), releasing an ϳ20-kDa D3 domain fragment containing three EGF repeats.…”

mentioning

confidence: 99%

Neutrophil Elastase Cleaves Laminin-332 (Laminin-5) Generating Peptides That Are Chemotactic for Neutrophils

Mydel

Shipley

Adair-Kirk

et al. 2008

Journal of Biological Chemistry

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Proteolytic processing of laminin-332 by matrix metalloproteinase (MMP)-2 and MMP-14 has been shown to yield fragments that are promigratory for epithelial cells. During acute and chronic inflammation, proteases are elaborated by neutrophils and macrophages that can degrade basement membranes. We investigated the susceptibility of laminin-332 to degradation by the following neutrophil and macrophage proteases: neutrophil elastase (NE), cathepsin G, proteinase-3, and MMPs-2, -8, -9, and -12. Protease-specific differences were seen in the capacity to cleave the individual chains of laminin-332. NE and MMP-12 showed the greatest activity toward the ␥2 chain, generating a fragment similar in size to the ␥2x fragment generated by MMP-2. The digestion pattern of laminin-332 by degranulated neutrophils was nearly identical to that generated with NE alone. Digestion by supernatants of degranulated neutrophils was blocked by an inhibitor of NE, and NE-deficient neutrophils were essentially unable to digest laminin-332, suggesting that NE is the major neutrophil-derived protease that degrades laminin-332. In vivo, laminin ␥2 fragments were found in the bronchoalveolar lavage fluid of wild-type mice treated with lipopolysaccharide, whereas that obtained from NE-deficient mice showed a different cleavage pattern. In addition, NE cleaved a synthetic peptide derived from the region of human laminin ␥2 containing the MMP-2 cleavage site, suggesting that NE may generate laminin-332 fragments that are also promigratory. Both laminin-332 fragments generated by NE digestion and NE-digested laminin ␥2 peptide were found to be chemotactic for neutrophils. Collectively, these data suggest that degradation of laminin-332 by NE generates fragments with important biological activities.Laminins are heterotrimeric proteins composed of ␣, ␤, and ␥ chains that are essential components of all basement membranes. Five ␣, four ␤, and three ␥ chains have been identified, which associate to form at least 15 laminin isoforms (1). Laminin-332 (formerly designated laminin-5) is composed of the ␣3, ␤3, and ␥2 chains and is a critical adhesive component of hemidesmosomes, specialized basement membrane structures underlying certain epithelia (2). Mutations of the LAMA3 (␣3), LAMB3 (␤3), or LAMC2 (␥2) genes result in the severe blistering disease epidermolysis bullosa (3, 4). Laminin-332 is presumably an essential laminin, as mice lacking expression of the ␥2 chain, which is unique to laminin-332, die a few days after birth (5).The ␣3, ␤3, and ␥2 chains are thought to self-associate via a central coiled-coil domain structure, with the short N-terminal arms of each extending from the coiled region to form a cruciform structure. Additionally, the C terminus of the ␣3 chain extends beyond the coiled region exposing five large globular (LG) 2 domains that are important in modulating the phenotype of attached cells. The unprocessed form of the ␣3 chain is thought to bind the ␣3␤1 integrin via the LG2 and LG3 domains, facilitating haptotactic migration of mu...

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Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration

Cited by 73 publications

References 44 publications

Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Neutrophil Elastase Cleaves Laminin-332 (Laminin-5) Generating Peptides That Are Chemotactic for Neutrophils

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