Claudin Promotes Activation of Pro-matrix Metalloproteinase-2 Mediated by Membrane-type Matrix Metalloproteinases

Miyamori, Hisashi; Takino, Takahisa; Kobayashi, Yuko; Tokai, Hideaki; Itoh, Yoshifumi; Seiki, Motoharu; Sato, Hiroshi

doi:10.1074/jbc.m103083200

Cited by 193 publications

(177 citation statements)

References 41 publications

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“…Astrocytes in culture exposed to interleukin-1b cease producing the gap junction protein, C x 43, and begin to produce claudin-1 (Duffy et al, 2000). Claudin promotes the activation of MMP-2, which would allow for amplification to take place, increasing the extent of the injury to the BBB (Miyamori et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat

Yang

Estrada

Thompson

et al. 2007

J Cereb Blood Flow Metab

920

772

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Matrix metalloproteinases (MMPs) disrupt the blood-brain barrier (BBB) during reperfusion. Occludin and claudins are recently described tight junction proteins (TJPs) that form the BBB. We hypothesized that the opening of the BBB was because of the degradation of TJPs by the MMPs. Spontaneously hypertensive rats had a 90 mins middle cerebral artery occlusion with reperfusion for 2, 3, or 24 h. Matrix metalloproteinases were measured by immunohistochemistry and in situ and gel zymography. Real-time polymerase chain reaction (PCR) measured mRNAs of MMP-2 and -9, furin, membrane-type MMP (MT1-MMP), occludin, and claudin-5. There was opening of the BBB in the piriform cortex after 3 h of reperfusion, and an MMP inhibitor, BB-1101 (30 mg/kg), prevented the opening. At 3 h, in situ zymograms showed gelatinase activity. Zymography and PCR showed greater increases in MMP-2 than in MMP-9. There were increased mRNA and immunohistochemistry for MT1-MMP and furin, which activate MMP-2. Claudin-5 and occludin mRNA expression decreased at 2 h in both hemispheres with fragments of both proteins seen on Western blot by 3 h on the ischemic side; treatment with BB-1101 reversed the degradation of the TJPs. Immunohistochemistry at 3 h showed fragmented TJPs within the endothelial cell clefts. By 24 h, in situ zymography showed gelatinase activity and gel zymography showed elevated levels of MMP-9. Disrupted TJPs previously seen in endothelial cells appeared in the surrounding astrocytes. Our results provide direct evidence that MMPs open the BBB by degrading TJPs and that an MMP inhibitor prevents degradation of the TJPs by MMPs.

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat

Yang

Estrada

Thompson

et al. 2007

J Cereb Blood Flow Metab

920

772

View full text Add to dashboard Cite

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“…Immunostaining revealed MT1 -MMP to be localized predominantly in the tumor-cell cytoplasm but also in the stroma, while b-catenin was stained in both cytoplasm and nuclei of tumor cells (640) originally identified as an activator of MMP-2, which plays a role in degradation of type-IV collagen, a major component of basement membrane (Sato et al, 1994). MT1 -MMP recruits TIMP-2 for activation of proMMP-2, a process enhanced by claudins 71, 72, 73 and 75 (Miyamori et al, 2001). MT1 -MMP also activates proMMP-13 and degrades collagens type I, II, III, V, VII and X, fibronectin, vitronectin, and Laminins 1 and 5 (Knauper et al, 1996;Koshikawa et al, 2000;Ohuchi et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Identification of membrane-type matrix metalloproteinase-1 as a target of the β-catenin/Tcf4 complex in human colorectal cancers

et al. 2002

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Genetic alterations of APC and CTNNB1 (b-catenin) have been identified in a number of human cancers including tumors arising in the colon and liver. Mutations in these genes lead to abnormal accumulation of b-catenin and constitutive activation of target genes in the Wnt signaling pathway. To clarify the precise role of accumulated bcatenin in colorectal carcinogenesis, we searched for genes involved in the b-catenin/Tcf signaling pathway by cDNA microarray. MT1 -MMP (membrane-type matrix metalloproteinase) was among 84 genes that were downregulated after b-catenin had been depleted by transduction of wild-type APC in SW480 cells. Expression of MT1 -MMP was elevated in 22 of 24 colon carcinomas we examined. Reporter assays and an electromobility-shift assay revealed a DNA fragment between 71169 bp and 71163 bp in the 5' flanking region of this gene to be a target of the b-catenin/Tcf4 complex. Our results indicate that MT1 -MMP is a direct down-stream target in the Wnt signaling pathway, and that one of the ways accumulated b-catenin contributes to colorectal carcinogenesis is by transactivating this gene.

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“…Claudin-1 expression leads to increases in matrix metalloproteinases Miyamori et al (2001) have linked claudin-1 to increases in matrix metalloproteinase 2 (MMP-2) and MMP-2 is crucial for the CXCL12-mediated migration of melanoma cells (Bartolome et al, 2006). To confirm the correlation between the expression of MMP-2 and motility of melanoma cells in our system, levels of MMP-2 were examined among a panel of cell lines, and compared to their motility in a wound-healing assay.…”

Section: Claudin-1 Expression Is Regulated By Pkc In Melanomamentioning

confidence: 99%

Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility

et al. 2006

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Serial analysis of gene expression followed by pathway analysis implicated the tight junction protein claudin-1 (CLDN1) in melanoma progression. Tight junction proteins regulate the paracellular transport of molecules, but staining of a tissue microarray revealed that claudin-1 was overexpressed in melanoma, and aberrantly expressed in the cytoplasm of malignant cells, suggesting a role other than transport. Indeed, melanoma cells in culture demonstrate no tight junction function. It has been shown that protein kinase C (PKC) can affect expression of claudin-1 in rat choroid plexus cells, and we observed a correlation between levels of activated PKC and claudin expression in our melanoma cells. To determine if PKC could affect the expression of CLDN1 in human melanoma, cells lacking endogenous claudin-1 were treated with 200 nM phorbol myristic acid (PMA). PKC activation by PMA caused an increase in CLDN1 transcription in 30 min, and an increase in claudin-1 protein by 12 h. Inhibition of PKC signaling in cells with high claudin-1 expression resulted in decreased claudin-1 expression. CLDN1 appears to contribute to melanoma cell invasion, as transient transfection of melanoma cells with CLDN1 increased metalloproteinase 2 (MMP-2) secretion and activation, and subsequently, motility of melanoma cells as demonstrated by wound-healing assays. Conversely, knockdown of CLDN1 by siRNA resulted in the inhibition of motility, as well as decreases in MMP-2 secretion and activation. These data implicate claudin-1 in melanoma progression.

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Claudin Promotes Activation of Pro-matrix Metalloproteinase-2 Mediated by Membrane-type Matrix Metalloproteinases

Abstract: Matrix metalloproteinases (MMPs) 1 are a family of Zn 2ϩ

Cited by 193 publications

References 41 publications

Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat

Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat

Identification of membrane-type matrix metalloproteinase-1 as a target of the β-catenin/Tcf4 complex in human colorectal cancers

Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility

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