Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

Remacle, Albert G.; Rozanov, Dmitry V.; Fugère, Martin; Day, Robert; Strongin, Alex Y.

doi:10.1038/sj.onc.1209572

Cited by 62 publications

(58 citation statements)

References 52 publications

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“…We also determined that glycosylation, rather than the furin cleavage of the prodomain part of the (63)(64)(65)(66)(67). In agreement, our recent data confirmed that the 89 RRPRC 93 site is inaccessible to cleavage by furin and furin-like PCs in the MT1-MMP proenzyme (51).…”

Section: Discussionsupporting

confidence: 77%

O-Glycosylation Regulates Autolysis of Cellular Membrane Type-1 Matrix Metalloproteinase (MT1-MMP)

Remacle

Chekanov

Golubkov

et al. 2006

Journal of Biological Chemistry

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MT1-MMP is a key enzyme in cancer cell invasion and metastasis. The activity of cellular MT1-MMP is regulated by furin-like proprotein convertases, TIMPs, shedding, autoproteolysis, dimerization, exocytosis, endocytosis, and recycling. Our data demonstrate that, in addition to these already known mechanisms, MT1-MMP is regulated by O-glycosylation of its hinge region. Insignificant autolytic degradation is characteristic for naturally expressed, glycosylated, MT1-MMP. In turn, extensive autolytic degradation, which leads to the inactivation of the protease and the generation of its C-terminal membrane-tethered degraded species, is a feature of overexpressed MT1-MMP. We have determined that incomplete glycosylation stimulates extensive autocatalytic degradation and self-inactivation of MT1-MMP. Self-proteolysis commences during the secretory process of MT1-MMP through the cell compartment to the plasma membrane. The strongly negatively charged sialic acid is the most important functional moiety of the glycopart of MT1-MMP. We hypothesize that sialic acid of the O-glycosylation cassette restricts the access of the catalytic domain to the hinge region and to the autolytic cleavage site and protects MT1-MMP from autolysis. Overall, our results point out that there is a delicate balance between glycosylation and self-proteolysis of MT1-MMP in cancer cells and that when this balance is upset the catalytically potent MT1-MMP pool is self-proteolyzed.Membrane-tethered MT1-MMP, 2 the most abundant member of the membrane-type (MT) matrix metalloproteinase subfamily, is distinguished from soluble MMPs by a short transmembrane domain and a cytoplasmic tail (1, 2). MT1-MMP functions in cancer cells as an important mediator of proteolytic events on the cell surface (3, 4), and it is directly engaged in the cleavage of cell surface receptors and the pericellular proteolysis of the extracellular matrix components (5-7). MT1-MMP expression is associated with a variety of pathophysiological conditions and especially with cell locomotion, tumor growth, and metastasis (4, 5, 8 -11).MT1-MMP and related membrane-tethered MMPs are regulated, both as proteinases and as membrane proteins, at the transcriptional and post-transcriptional levels by multifaceted coordinated mechanisms (12-22). The trafficking and the internalization of MT1-MMP have been identified as two additional mechanisms that regulate its biological functions. Both clathrin-coated pits and caveolae are involved in the internalization of 19,[23][24][25][26][27][28].To exercise its proteolytic activity, MT1-MMP requires the proteolytic removal of its N-terminal prodomain sequence (29). Because the prodomain part of MT1-MMP has the furin-cleavage motif, furin and related proprotein convertases (PCs) are the physiological activators of latent MT1-MMP (13, 30 -32). Proteolytic processing by the PCs leads to the activation of the latent MT1-MMP zymogen, which occurs primarily in the trans-Golgi network during the secretory passage of MT1-MMP (30, 33). The levels of expressio...

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Section: Discussionsupporting

confidence: 77%

O-Glycosylation Regulates Autolysis of Cellular Membrane Type-1 Matrix Metalloproteinase (MT1-MMP)

Remacle

Chekanov

Golubkov

et al. 2006

Journal of Biological Chemistry

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“…removed by furins, generating the active form of MT1-MMP Osenkowski et al, 2004). Once activated, MT1-MMP translocates to the surface where it can cleave ECM proteins (Remacle et al, 2006). In addition, active MT1-MMP undergoes endocytosis and can be recycled from the cell surface to early and late endosomes (Remacle et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

Dave

Abbey

Duran

et al. 2016

Journal of Cell Science

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During angiogenesis, endothelial cells must coordinate matrix proteolysis with migration. Here, we tested whether the focal adhesion scaffold protein Hic-5 (also known as TGFB1I1) regulated endothelial sprouting in three dimensions. Hic-5 silencing reduced endothelial sprouting and lumen formation, and sprouting defects were rescued by the return of Hic-5 expression. Pro-angiogenic factors enhanced colocalization and complex formation between membrane type-1 matrix metalloproteinase (MT1-MMP, also known as MMP14) and Hic-5, but not between paxillin and MT1-MMP. The LIM2 and LIM3 domains of Hic-5 were necessary and sufficient for Hic-5 to form a complex with MT1-MMP. The degree of interaction between MT1-MMP and Hic-5 and the localization of the complex within detergent-resistant membrane fractions were enhanced during endothelial sprouting, and Hic-5 depletion lowered the surface levels of MT1-MMP. In addition, we observed that loss of Hic-5 partially reduced complex formation between MT1-MMP and focal adhesion kinase (FAK, also known as PTK2), suggesting that Hic-5 bridges MT1-MMP and FAK. Finally, Hic-5 LIM2-LIM3 deletion mutants reduced sprout initiation. Hic-5, MT1-MMP and FAK colocalized in angiogenic vessels during porcine pregnancy, supporting that this complex assembles during angiogenesis in vivo. Collectively, Hic-5 appears to enhance complex formation between MT1-MMP and FAK in activated endothelial cells, which likely coordinates matrix proteolysis and cell motility.

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“…Similar to other MMPs, MT1-MMP is synthesized in an inactive form. However, it is constitutively activated by a furin-like pathway [27]. The constitutively active MT1-MMP accumulates at the invadopodia of tumor cells and activates pro-MMP-2 produced by stromal cells in the microenvironment (Figure 1) Active MMP-2 then degrades extracellular matrix components, allowing the cells to breach the ECM [26;28].…”

Section: Microenvironment Of Primary Breast and Prostate Cancersmentioning

confidence: 99%

Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases

Wilson

Singh

2008

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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SummaryAs cells undergo oncogenic transformation and as transformed cells arrive at metastatic sites, a complex interplay occurs with the surrounding stroma. This dialogue between tumor and stroma ultimately dictates the success of the tumor cells in the given microenvironment. As a result, understanding the molecular mechanisms at work is important for developing new therapeutic modalities. Proteases are major players in the interaction between tumor and stroma. This review will focus on the role of proteases in modulating tumor-stromal interactions of both primary breast and prostate tumors as well as at bone metastatic sites in a way that favors tumor growth.

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Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

Cited by 62 publications

References 52 publications

O-Glycosylation Regulates Autolysis of Cellular Membrane Type-1 Matrix Metalloproteinase (MT1-MMP)

O-Glycosylation Regulates Autolysis of Cellular Membrane Type-1 Matrix Metalloproteinase (MT1-MMP)

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases

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