Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin.

Huhtala, Pirkko; Humphries, Martin J.; McCarthy, James B.; Tremble, Patrice; Werb, Zena; Damsky, Caroline H.

doi:10.1083/jcb.129.3.867

Cited by 366 publications

(223 citation statements)

References 74 publications

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“…Fn is a multifunctional protein whose activities are due to functional domains present both in the native ''full-length'' protein 16,17 and its multiple sub-fragments. Indeed, when released by limited proteolysis, these functional domains display specific activities, latent in the native Fn.…”

Section: Discussionmentioning

confidence: 99%

Migration‐stimulating factor displays HEXXH‐dependent catalytic activity important for promoting tumor cell migration

Houard

Germain

Gervais

et al. 2005

Intl Journal of Cancer

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Like most extracellular matrix (ECM) components, fibronectin (Fn) is proteolyzed generating specific activities. Fibronectin proteinase (Fn-proteinase) represents such a cryptic activity located in the gelatin-binding domain (GBD) of Fn and displays a zinc metalloproteinase activity. The migration-stimulating factor (MSF) is a truncated Fn isoform generated by alternative mRNA splicing and corresponds to the N-terminal part of Fn that comprises the GBD. We show that several human mammary epithelial cells express MSF and constitutively produce Fn-proteinase activity. Furthermore, recombinant MSF produced by HEK-293 and MCF-7 cells possesses a constitutive Fn-proteinase activity. Mutating the putative zinc-binding motif, HEXXH, of the protein abolishes its activity thereby demonstrating its specificity. Using PCR, we showed that MSF is barely expressed in normal breast tissues, whereas its expression is significantly increased in tumors. Furthermore, an association between MSF expression and invasive capacity is observed in various breast adenocarcinoma cell lines. Indeed, when stably transfected in non-invasive MCF-7 cells, MSF promotes cell migration in a mechanism mostly dependent on its Fn-proteinase activity. In summary, our study shows that: (i) MSF displays constitutive Fn-proteinase activity; (ii) MSF expression is induced in human breast cancer; and (iii) MSF confers pro-migratory activity that depends mostly on its Fn-proteinase activity. These results suggest that MSF may be involved in tumor progression. ' 2005 Wiley-Liss, Inc.Key words: fibronectin; alternative splicing; Fn-proteinase; migration-stimulating factor; cancer Fibronectin (Fn) is an adhesive glycoprotein, secreted as a dimer, present in body fluids and within extracellular matrices. Each monomer ( 250 kDa) is organized into proteolysis-resistant functional domains. These domains can bind fibrin, collagens, integrins and proteoglycans, accounting for the wide range of Fn functions (Fig. 1a). 1 In addition to these well-characterized properties of ''fulllength'' Fn, proteolytically generated Fn fragments show additional biological activities. For instance, the gelatin-binding domain (GBD) influences cell proliferation and migration, 2 and induces cartilage catabolism. 3 In addition, the GBD isolated after Fn proteolysis or produced in recombinant cells, referred to fibronectin proteinase (Fn-proteinase), 4 displays a zinc-dependent collagenase/gelatinase activity. [5][6][7] Fn-proteinase activity is inhibited by a specific phosphinic pseudo peptide. 5 This activity is involved in the degradation of cartilage induced by the GBD. 8 In addition, we showed recently that Fn-proteinase is activated by plasmin and therefore may play a role in tissue remodeling. 4 Zhao et al. 9 recently cloned and characterized a C-terminus truncated Fn isoform generated by alternative splicing in zebrafish. This isoform, called Fn2, is a 120-kDa monomeric protein with distinct properties compared to ''full-length '' Fn. 9 This raised the possibility that Fn fragm...

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Section: Discussionmentioning

confidence: 99%

Migration‐stimulating factor displays HEXXH‐dependent catalytic activity important for promoting tumor cell migration

Houard

Germain

Gervais

et al. 2005

Intl Journal of Cancer

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“…a3b1 integrin was shown to participate in phagocytosis of extracellular matrix (Coopman et al, 1996). a2b1, a3b1, a4b1, and a5b1 integrin were found to be involved in the regulation of matrix metalloprotease expression (Larjava et al, 1993;Huhtala et al, 1995;Riikonen et al, 1995). In addition, activation of a6b1 integrin increased invasiveness of LOX human melanoma cells correlating with a 2 ± 3-fold elevation of extracellular matrix degradation and invadopodial activity (Nakahra et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Third, integrins are necessary for basement membrane penetration, since RGD peptides interfering with ligand binding to certain integrins prevented this process in vitro (Gehlsen et al, 1988). And ®nally, integrins are involved in the regulation of protease expression and their localized activities, as demonstrated in tissue culture experiments (Huhtala et al, 1995;Riikonen et al, 1995;Brooks et al, 1996;Coopman et al, 1996;Nakahara et al, 1996). In vivo changes in the metastatic potential of tumor cells often correlated with changes of the integrin expression pattern.…”

Section: Introductionmentioning

confidence: 99%

β1 integrin promotes but is not essential for metastasis of ras-myc transformed fibroblasts

Brakebusch

Wennerberg

Krell³

et al. 1999

Oncogene

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To investigate the role of b1 integrin during tumor metastasis, we established a ras-myc transformed ®broblastoid cell line with a disrupted b1 integrin gene on both alleles (GERM 11). Stable transfection of this cell line with an expression vector encoding b1A integrin resulted in b1A integrin-expressing sublines. Tumors were induced by subcutaneous injection of GERM 11 cells and 3 independent b1 integrin expressing sublines (GERM 116, 1A10, 2F2) into syngeneic mice. After 10 days tumors were surgically removed. While average weights of GERM 11 and GERM 116 tumors were similar, tumors induced by the high expressing clones 1A10 and 2F2 were markedly smaller, suggesting an inverse correlation of tumor growth and b1 integrin expression. The metastasis potential of all three b1 integrin-expressing GERM 11 sublines tested was signi®cantly higher than that of the b1-de®cient GERM 11 cells. GERM 116 tumors led in all animals to severe metastasis in lung and liver, while GERM 11 tumors induced only a few metastatic foci in the lung. Stroma of both tumors contained nidogen and high amounts of tenascin C, but only a few very low levels of ®bronectin, laminin-1, and collagen type I. b1 integrin, therefore, increases but is not essential for metastasis of ras-myc transformed ®broblasts.

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“…39 A number of studies have addressed the correlation of MMP expression with invasive ability of malignant tumors. [40][41][42][43] It has been shown that signal transduction through ␤1 integrins induces MMP production 44,45 and activation of MMP proenzymes. 46 Furthermore, activated MMPs can be localized with ␤1 integrins at the focal contacts on the surface of invasive cells.…”

Section: Discussionmentioning

confidence: 99%

Role of β1 Integrins in Adhesion and Invasion of Hepatocellular Carcinoma Cells

1999

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To investigate the role of integrins in hepatocellular carcinoma (HCC) invasion, we analyzed the relationship between the expression and activity of ␤1 integrins and the invasive ability of multiple HCC cell lines. Human HCC cell lines, PLC/PRF/5, Hep3B, HepG2, HLE, HuH7, and C3A cells, had high expression of ␤1 and ␣6 subunits, and various levels of ␣1, ␣2, ␣3, and ␣5 expression as determined by cell surface flow cytometry. Activity of ␤1 integrins was evaluated by cell adhesion to collagen, fibronectin, and laminin in the presence or absence of the stimulatory anti-␤1 monoclonal antibody ( Tumor invasion and metastasis are complex processes requiring the ability of tumor cells to interact with endothelial cells and extracellular matrix. The major cell surface receptors that mediate these interactions are integrins. They are heterodimeric transmembrane receptors consisting of ␣ and ␤ subunits, which produce more than 20 different heterodimers and bind specific ligands. 1,2 Each subunit is a glycoprotein with a large extracellular domain and a relatively small cytoplasmic domain. It has been shown that integrins can transduce signals and play principal roles in biological features of tumors, especially in growth, differentiation, and invasive and metastatic events of malignant cells. 2,3 Changes in expression of integrins have been linked to both tumor suppression and tumor progression in different human malignancies. 4,5 Several studies have described altered expression of ␤1 integrins in hepatocellular carcinoma (HCC). Reduced expression of ␣2, ␣3, and ␣5 subunits 6,7 and overexpression of ␣6 subunits of ␤1 integrins 8 have been shown in HCC with aggressive phenotypes. Nonpolarized aberrant distribution of ␤1 subunit has been shown to correlate with tumor growth rate, grade, and size in HCC. 9 These observations suggest important roles of ␤1 integrins in growth and invasiveness of HCC. Recently, several studies have indicated the modulation of expression and function of ␤1 integrins on HCC cells during metastatic events. Following the adhesion to vascular endothelial cells, HCC cells receive stimulation from cytokines produced by the endothelial cells. The resultant increase of ␣2␤1 integrin expression on HCC cells may facilitate migration of these cells to extravascular tissues. 10 On the contrary, the cell adhesion regulator, the gene of which is located on 16q, suppresses the process of integrin-mediated cell adhesion and has an inhibitory effect on the progression of HCC. 11

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Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin.

Cited by 366 publications

References 74 publications

Migration‐stimulating factor displays HEXXH‐dependent catalytic activity important for promoting tumor cell migration

Migration‐stimulating factor displays HEXXH‐dependent catalytic activity important for promoting tumor cell migration

β1 integrin promotes but is not essential for metastasis of ras-myc transformed fibroblasts

Role of β1 Integrins in Adhesion and Invasion of Hepatocellular Carcinoma Cells

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