Involvement of the MAP kinase ERK2 in MUC1 mucin signaling.
MUC1 mucin is a receptor-like glycoprotein expressed abundantly in various cancer cell lines as well as in glandular secretory epithelial cells, including airway surface epithelial cells. The role of this cell surface mucin in the airway is not known. In an attempt to understand the signaling mechanism of MUC1 mucin, we established a stable cell line from COS-7 cells expressing a chimeric receptor consisting of the extracellular and transmembrane domains of CD8 and the cytoplasmic (CT) domain of MUC1 mucin (CD8/MUC1 cells). We previously observed that treatment of these cells with anti-CD8 antibody resulted in tyrosine phosphorylation of the CT domain of the chimera. Here we report that treatment of CD8/MUC1 cells with anti-CD8 resulted in activation of extracellular signal-regulated kinase (ERK) 2 as assessed by immunoblotting, kinase assay, and immunocytochemistry. The activation of ERK2 was completely blocked either by a dominant negative Ras mutant or in the presence of a mitogen-activated protein kinase kinase (MEK) inhibitor. We conclude that tyrosine phosphorylation of the CT domain of MUC1 mucin leads to activation of a mitogen-activated protein kinase pathway through the Ras-MEK-ERK2 pathway. Combined with the existing data by others, it is suggested that one of the roles of MUC1 mucin may be regulation of cell growth and differentiation via a common signaling pathway, namely the Grb2-Sos-Ras-MEK-ERK2 pathway.
Meerzaman
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Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, USA.
Shapiro
P S
PS
Kim
K C
KC
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D019556:COS Cells; D002678:Chimera; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D018396:Mucin-1 / Q000235:genetics / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000494:pharmacology
D000906:Antibodies; D002070:Butadienes; D016827:CD8 Antigens; D004791:Enzyme Inhibitors; D018396:Mucin-1; D009570:Nitriles; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins