Adhesion-dependent activation of the ERK1/2 cascade is by-passed in melanoma cells.
Normal cells are dependent upon integrin-mediated adhesion to the extracellular matrix for cell proliferation and survival. Integrins regulate these processes partially through control of extracellular signal-regulated kinases 1 and 2 (ERK1/2). A trait of malignant cells is their ability to undergo anchorage-independent growth. Melanomas are tumors arising from normal melanocytes that, if undetected at an early stage, are highly invasive and poorly treatable. Proliferation of melanoma cells and melanocytes is dependent upon ERK1/2 signaling, and mutation of B-Raf, a component of the ERK1/2 pathway, is commonly found in melanomas. We addressed the role of integrin-mediated adhesion in ERK1/2 signaling in human melanoma cells and primary melanocytes. Basal ERK1/2 activity was low, and growth factor activation was adhesion-dependent in normal human melanocytes. By contrast in mutant B-Raf-expressing melanoma cells (SK-MEL-24 and SK-MEL-28), the ERK1/2 pathway was constitutively active, and adhesion-dependent regulation of ERK1/2 activity was by-passed. Furthermore, in melanoma cells, ERK1/2 translocated to the nucleus and regulated transcription events in an adhesion-independent manner. Expression of mutant V599E B-Raf in normal melanocytes was sufficient to promote adhesion-independent ERK1/2 signaling. These results indicate that alterations in the adhesion requirement for ERK1/2 signaling in melanocytes are associated with the acquisition of malignant cell behavior.
Conner
Sean R
SR
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208, USA.
Scott
Glynis
G
Aplin
Andrew E
AE
D015153:Blotting, Western; D002448:Cell Adhesion; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D008156:Luciferases; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases