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Laminin-Induced Signaling in Tumor Cells

The Role of the M_r 67,000 Laminin Receptor

¹ Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel, and ² Department of Pathology, The Norwegian Radium Hospital, Montebello, Oslo, Norway

The expression of the M_r 67,000 laminin receptor, a nonintegrin laminin receptor, was found to be up-regulated in neoplastic cells and to directly correlate with invasion and metastatic potential. In the present study, we investigated the role of laminin receptor in mediating laminin effects and the involvement of the mitogen-activated protein kinases (MAPK) cascades and dual-specificity phosphatases in laminin signaling in human melanoma cells. Using stable transfection of A375SM melanoma cells, we established lines expressing reduced or elevated laminin receptor. The antisense-transfected cells demonstrated reduced attachment to laminin and reduced invasion through Matrigel-coated filters. In addition, both matrix metalloproteinase-2 (MMP-2) mRNA expression and activity were significantly reduced in the antisense-transfected cells. Antisense-transfected cells showed a reduction in mRNA level of the 6B integrin subunit isoform, whereas no change in the mRNA level of the 6A isoform was observed. We found that exogenous laminin reduced the phosphorylated (active) form of extracellular signal-regulated kinase, c-Jun NH₂-terminal protein kinase, and p38 in all of the cells, irrespective of the expression of the laminin receptor. Furthermore, the phosphorylation of extracellular signal-regulated kinase, c-Jun NH₂-terminal protein kinase, and p38 was significantly higher in the cell lines expressing reduced laminin receptor, regardless of the exposure to exogenous laminin. This increase of MAPK phosphorylation was accompanied by a significant reduction in MKP-1 phosphatase mRNA level and a significant increase in PAC-1 phosphatase mRNA level. In conclusion, our results confirm the involvement of the laminin receptor in different mechanisms related to tumor dissemination and provide first evidence of the involvement of MAPK and dual-specificity phosphatases in its signal transduction pathway.

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