Laminin-induced signaling in tumor cells: the role of the M(r) 67,000 laminin receptor.
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 alpha6B integrin subunit isoform, whereas no change in the mRNA level of the alpha6A isoform was observed. We found that exogenous laminin reduced the phosphorylated (active) form of extracellular signal-regulated kinase, c-Jun NH(2)-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 NH(2)-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.
Givant-Horwitz
Vered
V
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Davidson
Ben
B
Reich
Reuven
R
D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D054638:Dual Specificity Phosphatase 1; D054641:Dual Specificity Phosphatase 2; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D039503:Integrin alpha6 / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D007797:Laminin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008970:Molecular Weight; D009361:Neoplasm Invasiveness; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017474:Receptors, Laminin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D039503:Integrin alpha6; D007797:Laminin; D012333:RNA, Messenger; D017474:Receptors, Laminin; C121346:laminin 1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C517019:DUSP1 protein, human; C517032:DUSP2 protein, human; D054638:Dual Specificity Phosphatase 1; D054641:Dual Specificity Phosphatase 2; D017027:Protein Tyrosine Phosphatases; D020778:Matrix Metalloproteinase 2