Role of Integrins in Regulating Proteases to Mediate Extracellular Matrix Remodeling

Yue, Jiao; Zhang, Kun; Chen, Jianfeng

doi:10.1007/s12307-012-0101-3

Cited by 61 publications

(44 citation statements)

References 107 publications

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“…Also the activity of small Rho-GTPases was deranged by the use of M25 peptide as well as by uPAR-aODN, thus partially inhibiting mesenchymal migration and totally inhibiting the amoeboid one. As the M25 peptide is specific for inhibition of uPAR-integrin α-chain interaction, its limited effects of on mesenchymal migration may be accounted for by the failure of the peptide to inhibit integrin-MMPs interactions that also regulate mesenchymal motility [43,44]. …”

Section: Discussionmentioning

confidence: 99%

The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style

et al. 2014

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The receptor for the urokinase plasminogen activator (uPAR) is up-regulated in malignant tumors. Historically the function of uPAR in cancer cell invasion is strictly related to its property to promote uPA-dependent proteolysis of extracellular matrix and to open a path to malignant cells. These features are typical of mesenchymal motility. Here we show that the full-length form of uPAR is required when prostate and melanoma cancer cells convert their migration style from the “path generating” mesenchymal to the “path finding” amoeboid one, thus conferring a plasticity to tumor cell invasiveness across three-dimensional matrices. Indeed, in response to a protease inhibitors-rich milieu, prostate and melanoma cells activated an amoeboid invasion program connoted by retraction of cell protrusions, RhoA-mediated rounding of the cell body, formation of a cortical ring of actin and a reduction of Rac-1 activation. While the mesenchymal movement was reduced upon silencing of uPAR expression, the amoeboid one was almost completely abolished, in parallel with a deregulation of small Rho-GTPases activity. In melanoma and prostate cancer cells we have shown uPAR colocalization with β1/β3 integrins and actin cytoskeleton, as well integrins-actin co-localization under both mesenchymal and amoeboid conditions. Such co-localizations were lost upon treatment of cells with a peptide that inhibits uPAR-integrin interactions. Similarly to uPAR silencing, the peptide reduced mesenchymal invasion and almost abolished the amoeboid one. These results indicate that full-length uPAR bridges the mesenchymal and amoeboid style of movement by an inward-oriented activity based on its property to promote integrin-actin interactions and the following cytoskeleton assembly.

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Section: Discussionmentioning

confidence: 99%

The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style

et al. 2014

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“…MT1-MMP on cell surfaces is replenished by autodegradation or clathrin-dependent internalization, and its concentration is stabilized by the tissue inhibitor of MMP (TIMP)-2 [5, 6]. Malignant human gliomas express membrane-anchored MMPs and their endogenous TIMPs [7–10]. Many MMP inhibitors have been developed for human clinical trials, but effective candidates have not been obtained [10, 11].…”

Section: Introductionmentioning

confidence: 99%

“…Malignant human gliomas express membrane-anchored MMPs and their endogenous TIMPs [7–10]. Many MMP inhibitors have been developed for human clinical trials, but effective candidates have not been obtained [10, 11]. …”

Section: Introductionmentioning

confidence: 99%

Chlorotoxin Fused to IgG-Fc Inhibits Glioblastoma Cell Motility via Receptor-Mediated Endocytosis

Kasai

Nakamura

Vaidyanath

et al. 2012

Journal of Drug Delivery

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Chlorotoxin is a 36-amino acid peptide derived from Leiurus quinquestriatus (scorpion) venom, which has been shown to inhibit low-conductance chloride channels in colonic epithelial cells. Chlorotoxin also binds to matrix metalloproteinase-2 and other proteins on glioma cell surfaces. Glioma cells are considered to require the activation of matrix metalloproteinase-2 during invasion and migration. In this study, for targeting glioma, we designed two types of recombinant chlorotoxin fused to human IgG-Fcs with/without a hinge region. Chlorotoxin fused to IgG-Fcs was designed as a dimer of 60 kDa with a hinge region and a monomer of 30 kDa without a hinge region. The monomeric and dimeric forms of chlorotoxin inhibited cell proliferation at 300 nM and induced internalization in human glioma A172 cells. The monomer had a greater inhibitory effect than the dimer; therefore, monomeric chlorotoxin fused to IgG-Fc was multivalently displayed on the surface of bionanocapsules to develop a drug delivery system that targeted matrix metalloproteinase-2. The target-dependent internalization of bionanocapsules in A172 cells was observed when chlorotoxin was displayed on the bionanocapsules. This study indicates that chlorotoxin fused to IgG-Fcs could be useful for the active targeting of glioblastoma cells.

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“…16,17 Hepsin also activates pro-urokinase-type plasminogen activator (pro-uPA), which triggers plasminogen to plasmin conversion linked to degradation and remodelling of BM. [18][19][20] In addition to indirect routes involving matriptase, prostasin and other serine proteases, hepsin may directly shape BM by cleaving laminin-332, a component of BM and a ligand for hemidesmosomal α6β4 integrins. 21 While the existing evidence indicates that elevated level of hepsin expression promotes epithelial carcinogenesis, the mechanistic underpinnings of the oncogenicity of hepsin have remained unclear.…”

Section: Introductionmentioning

confidence: 99%

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion

et al. 2015

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Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

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Role of Integrins in Regulating Proteases to Mediate Extracellular Matrix Remodeling

Cited by 61 publications

References 107 publications

The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style

The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style

Chlorotoxin Fused to IgG-Fc Inhibits Glioblastoma Cell Motility via Receptor-Mediated Endocytosis

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion

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