Membrane type-1 matrix metalloproteinase (MT1-MMP) processing of pro-alphav integrin regulates cross-talk between alphavbeta3 and alpha2beta1 integrins in breast carcinoma cells.

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Experimental Cell Research (Impact Factor: 3.37). 12/2003; 291(1):167-75.
Source: PubMed

ABSTRACT We have recently demonstrated that in breast carcinoma MCF7 cells MT1-MMP processes the alphav, alpha3, and alpha5 integrin precursors generating the respective mature S-S-linked heavy and light alpha-chains. The precursor of alpha2 integrin subunit was found resistant to MT1-MMP proteolysis. The processing of the alphav subunit by MT1-MMP facilitated alphavbeta3-dependent adhesion, activation of FAK signaling pathway, and migration of MCF7 cells on vitronectin. To elucidate further the effects of MT1-MMP on cellular integrins, we examined the functional activity of alpha5beta1 and alpha2beta1 integrins in MCF7 cells expressing MT1-MMP. Either expression of MT1-MMP alone or its coexpression with alphavbeta3 failed to affect the functionality of alpha5beta1 integrin, and adhesion of cells to fibronectin. MT1-MMP, however, profoundly affected the cross-talk involving alphavbeta3 and alpha2beta1 integrins. In MT1-MMP-deficient cells, integrin alphavbeta3 suppressed the functional activity of the collagen-binding alpha2beta1 integrin receptor and diminished cell adhesion to type I collagen. Coexpression of MT1-MMP with integrin alphavbeta3 restored the functionality of alpha2beta1 integrin and, consequently, the ability of MCF7 cells to adhere efficiently to collagen. We conclude that the MT1-MMP-controlled cross-talk between alphavbeta3 and alpha2beta1 integrins supports binding of aggressive, MT1-MMP-, and alphavbeta3 integrin-expressing malignant cells on type I collagen, the most common substratum of the extracellular matrix.

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    • "Previous studies suggest that one integrin can regulate the activation state of other integrins in the same cell, a mechanism called transdominant inhibition (Gonzalez et al., 2009). For example, increased expression of αvβ3 suppresses α2βl-dependent adhesion of breast carcinoma cells (Baciu et al., 2003). We recently demonstrated that αvβ5/β6 integrins down-regulate the α2β1- dependent cell migration of colonic adenocarcinoma cells. "
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    ABSTRACT: Previous studies have reported that cross-talk between integrins may be an important regulator of integrin-ligand binding and subsequent signalling events that control a variety of cell functions in many tissues. We previously demonstrated that αvβ5/β6 integrin represses α2β1-dependent cell migration. The αv subunits undergo an endoproteolytic cleavage by protein convertases, whose role in tumoral invasion has remained controversial. Inhibition of convertases by the convertase inhibitor α1-PDX (α1-antitrypsin Portland variant), leading to the cell-surface expression of an uncleaved form of the αv integrin, stimulated cell migration toward type I collagen. Under convertase inhibition, α2β1 engagement led to enhanced phosphorylation of both FAK (focal adhesion kinase) and MAPK (mitogen-activated protein kinase). This outside-in signalling stimulation was associated with increased levels of activated β1 integrin located in larger than usual focal-adhesion structures and a cell migration that was independent of the PI3K (phosphoinositide 3-kinase)/Akt (also called protein kinase B) pathway. The increase in cell migration observed upon convertases inhibition appears to be due to the up-regulation of β1 integrins and to their location in larger focal-adhesion structures. The endoproteolytic cleavage of αv subunits is necessary for αvβ5/β6 integrin to control α2β1 function and could thus play an essential role in colon cancer cell migration.
    Biology of the Cell 07/2011; 103(11):519-29. DOI:10.1042/BC20100147 · 3.87 Impact Factor
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    • "Integrin avb3 is fundamental in crossing the blood–brain barrier and it is also able to regulate the binding of a2b1 to fibronectin and the conversion of pro-av to the mature av subunit. This conversion is achieved by MT1-MMP in breast carcinoma cells (Baciu et al., 2003), but is usually performed by proprotein convertases (PCs) (Bassi et al., 2005). Infection of murine macrophages with T. gondii did not interfere initially with expression of av or b3 at the cell surface. "
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    ABSTRACT: Toxoplasmosis is a world wide spread zoonosis caused by Toxoplasma gondii, an obligate intracellular parasite that is able to disseminate into deep tissues and cross biological barriers, reaching immunoprivileged sites such as the brain and retina. The parasite is able to infect macrophages and dendritic cells for dispersal throughout the body. However, the molecular principals or outcomes of the subversion of the host cell are largely unknown. We evaluated the involvement of host invasive machinery in the migration of T. gondii infected murine cells from a monocytic/macrophage lineage. Migration in Matrigel of infected macrophages was augmented after 48 h of infection, and inhibition of metalloproteinases abolished migration. We also demonstrated that T. gondii infection induces a decreasing of CD44 at cell surface independent of the ERK signaling pathway, and that secretion of active MMP9 is augmented upon infection. Infected macrophages showed increased expression of MT1-MMP and ADAM10 membrane matrix metalloproteinases. Furthermore, processing of pro-alpha v and pro-beta 3 in T. gondii infected cells seems to depend on metalloproteinases to generate functional mature integrin alpha v beta 3 molecules, with no evidence of the involvement of proprotein convertase pathway.
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    • "MMP-3,-7 breast cancer (Noe et al.,2001) MMP-7 prostate (Davies et al.,2001) MMP-9 ovarian carcinoma (Symowicz et al.,2007) plasmin oral squamous cell carcinoma (Hayashido et al.,2005; Ryniers et al.,2002) melanoma (Billion et al.,2006) serum, ascites, urin several cancers (De Wever et al.,2007) review EpCAM Ectodomain shedding ADAM-17 colon carcinoma cells (Maetzel et al.,2009) ectosomes several cancer cell lines (Baj-Krzyworzeka et al.,2006) exosomes ovarian carcinoma (Runz et al.,2007) exosomes ovarian carcinoma ascites (Runz et al.,2007) ICAM-1 CD54 ectodomain shedding MMP-9 breast carcinoma cells (Fiore et al.,2002) serum, plasma several cancers (Witkowska and Borawska 2004) integrin, alpha 2 CD49b cell fragments melanoma (Friedl et al.,1997) integrin, alpha 3 CD49c ectodomain shedding MT1-MMP breast carcinoma (Baciu et al.,2003) integrin, alpha 4 CD49d ectodomain shedding uPA prostate carcinoma (Demetriou et al.,2004) tumor tissue prostate carcinoma (Demetriou et al.,2004) integrin, alpha 5 CD49e ectodomain shedding MT1-MMP breast carcinoma (Baciu et al.,2003) integrin, alpha V CD51 ectodomain shedding MT1-MMP breast carcinoma (Baciu et al.,2003; Deryugina et al.,2002; Ratnikov et al.,2002) ectosomes several tumor cell lines (Baj-Krzyworzeka et al.,2006) integrin, beta 1 CD29 ectosomes several tumor cell lines (Baj-Krzyworzeka et al.,2006) vesicles breast carcinoma (Dolo et al.,1998) cell fragments melanoma (Friedl et al.,1997; Mayer et al.,2004) integrin, beta 4 CD104 ectodomain shedding MMP-7 prostate carcinoma (von Bredow et al.,1997) L1CAM CD171 ectodomain shedding ADAM-10 several tumor cell lines (Mechtersheimer et al.,2001) ADAM-17 ovarian carcinoma (Stoeck et al.,2006) Plasmin melanoma (Nayeem et al.,1999) exosomes ADAM-10 ovarian carcinoma (Stoeck et al.,2006) exosomes ovarian carcinoma (Gutwein et al.,2005) melanoma, prostate carcinoma unpublished results exosomes ovarian carcinoma ascites (Gutwein et al.,2005) "
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