Membrane type‐1 matrix metalloprotease‐independent activation of pro‐matrix metalloprotease‐2 by proprotein convertases

Koo, Bon‐Hun; Kim, Hee‐Hyun; Park, Michael Y.; Jeon, Ok Hee; Kim, Doo‐Sik

doi:10.1111/j.1742-4658.2009.07335.x

Cited by 6 publications

(5 citation statements)

References 46 publications

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“…Knowing that furin PCs can directly and indirectly influence Mmp activation ( 30 – 32 ), we asked whether inhibiting their activity improved the molecular and cellular phenotypes associated with pmm2 deficiency. Remarkably, injection of a pan-reactive proconvertase inhibitor (PCI) into the hearts of 5 dpf pmm2 m/m embryos significantly improved cartilage morphology in 64% of the embryos analyzed ( Figure 5, A–C ).…”

Section: Resultsmentioning

confidence: 99%

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Protease-dependent defects in N-cadherin processing drive PMM2-CDG pathogenesis

Klaver¹,

Dukes-Rimsky²,

Kumar³

et al. 2021

JCI Insight

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The genetic bases for the congenital disorders of glycosylation (CDG) continue to expand, but how glycosylation defects cause patient phenotypes remains largely unknown. Here, we combined developmental phenotyping and biochemical studies in a potentially new zebrafish model ( pmm2 sa10150 ) of PMM2-CDG to uncover a protease-mediated pathogenic mechanism relevant to craniofacial and motility phenotypes in mutant embryos. Mutant embryos had reduced phosphomannomutase activity and modest decreases in N-glycan occupancy as detected by matrix-assisted laser desorption ionization mass spectrometry imaging. Cellular analyses of cartilage defects in pmm2 sa10150 embryos revealed a block in chondrogenesis that was associated with defective proteolytic processing, but seemingly normal N-glycosylation, of the cell adhesion molecule N-cadherin. The activities of the proconvertases and matrix metalloproteinases responsible for N-cadherin maturation were significantly altered in pmm2 sa10150 mutant embryos. Importantly, pharmacologic and genetic manipulation of proconvertase activity restored matrix metalloproteinase activity, N-cadherin processing, and cartilage pathology in pmm2 sa10150 embryos. Collectively, these studies demonstrate in CDG that targeted alterations in protease activity create a pathogenic cascade that affects the maturation of cell adhesion proteins critical for tissue development.

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Section: Resultsmentioning

confidence: 99%

“…Knowing that furin proconvertases can directly and indirectly influence Mmp activation (30)(31)(32), we asked whether inhibiting their activity improved the molecular and cellular phenotypes associated with pmm2 deficiency.…”

Section: Inhibition Of Furin Proconvertases Rescues Multiple Molecular and Cellular Phenotypesmentioning

confidence: 99%

Protease-dependent defects in N-cadherin processing drive PMM2-CDG pathogenesis

Klaver¹,

Dukes-Rimsky²,

Kumar³

et al. 2021

JCI Insight

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“…In addition, we studied the gene expression of two matrix metalloproteinases (MMP2 and MMP14), which are key factors in cancer invasion and metastasis [27] and substrates of PCs [28]–[30].…”

Section: Introductionmentioning

confidence: 99%

Alterations in Gene Expression of Proprotein Convertases in Human Lung Cancer Have a Limited Number of Scenarios

et al. 2013

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Proprotein convertases (PCs) is a protein family which includes nine highly specific subtilisin-like serine endopeptidases in mammals. The system of PCs is involved in carcinogenesis and levels of PC mRNAs alter in cancer, which suggests expression status of PCs as a possible marker for cancer typing and prognosis. The goal of this work was to assess the information value of expression profiling of PC genes. Quantitative polymerase chain reaction was used for the first time to analyze mRNA levels of all PC genes as well as matrix metalloproteinase genes MMP2 and MMP14, which are substrates of PCs, in 30 matched pairs of samples of human lung cancer tumor and adjacent tissues without pathology. Significant changes in the expression of PCs have been revealed in tumor tissues: increased FURIN mRNA level (p<0.00005) and decreased mRNA levels of PCSK2 (p<0.007), PCSK5 (p<0.0002), PCSK7 (p<0.002), PCSK9 (p<0.00008), and MBTPS1 (p<0.00004) as well as a tendency to increase in the level of PCSK1 mRNA. Four distinct groups of samples have been identified by cluster analysis of the expression patterns of PC genes in tumor vs. normal tissue. Three of these groups covering 80% of samples feature a strong elevation in the expression of a single gene in cancer: FURIN, PCSK1, or PCSK6. Thus, the changes in the expression of PC genes have a limited number of scenarios, which may reflect different pathways of tumor development and cryptic features of tumors. This finding allows to consider the mRNAs of PC genes as potentially important tumor markers.

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“…Membrane-type MMPs execute their activity bound to the membrane of the cells by a GPI anchor or by transmembrane domains. Moreover, other non-membrane-type MMPs such as MMP-2, -8 and -9 also bind to membrane proteins and exert their functions over the cell membrane [78,79]. Several secreted MMPs diffuse and exert proteolytic activity at significant distances from the cell secreting them.…”

Section: Regulation Of Mmps and Timpsmentioning

confidence: 99%

Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play

Chuliá-Peris

Carreres-Rey

Gabasa

et al. 2022

IJMS

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Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP actions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.

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Membrane type‐1 matrix metalloprotease‐independent activation of pro‐matrix metalloprotease‐2 by proprotein convertases

Cited by 6 publications

References 46 publications

Protease-dependent defects in N-cadherin processing drive PMM2-CDG pathogenesis

Protease-dependent defects in N-cadherin processing drive PMM2-CDG pathogenesis

Alterations in Gene Expression of Proprotein Convertases in Human Lung Cancer Have a Limited Number of Scenarios

Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play

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