title: Membrane cofactor protein (MCP; CD46): isoform-specific tyrosine phosphorylation.
abstract: Membrane cofactor protein (MCP; CD46) is a widely expressed type 1 transmembrane glycoprotein that inhibits complement activation on host cells. It also is a receptor for several pathogens including measles virus, Streptococcus pyogenes, Neisseria gonorrhea, and Neisseria meningitidis. That MCP may have signaling capability was suggested by its microbial interactions. That is, binding of MCP on human monocytes by measles virus hemagglutinin or cross-linking by an anti-MCP Ab resulted in IL-12 down-regulation, while binding to MCP by Neisseria on epithelial cells produced a calcium flux. Through alternative splicing, MCP is expressed on most cells with two distinct cytoplasmic tails of 16 (CYT-1) or 23 (CYT-2) amino acids. These play pivotal roles in intracellular precursor processing and basolateral localization. We investigated the putative signal transduction pathway mediated by MCP and demonstrate that CYT-2, but not CYT-1, is phosphorylated on tyrosine. We examined MCP tail peptides and performed Ab cross-linking experiments on several human cell lines and MCP isoform transfectants. We found an MCP peptide of CYT-2 was phosphorylated by a src kinase system. Western blots of the cells lines demonstrated that cells bearing CYT-2 were also phosphorylated on tyrosine. Additionally, we provide genetic and biochemical evidence that the src family of kinases is responsible for the latter phosphorylation events. In particular, the src kinase, Lck, is required for phosphorylation of MCP in the Jurkat T cell line. Taken together, these studies suggest a src family-dependent pathway for signaling through MCP.
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.forename: M K
authors.initials: MK
authors.lastname: Liszewski
authors.forename: A C
authors.initials: AC
authors.lastname: Chan
authors.forename: J P
authors.initials: JP
authors.lastname: Atkinson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D003169:Complement Inactivator Proteins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D013379:Substrate Specificity; D014443:Tyrosine / Q000378:metabolism*; D014638:Vanadates / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C497857:CD46 protein, human; D003169:Complement Inactivator Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D020033:Protein Isoforms; C076715:pervanadate; D014638:Vanadates; D014443:Tyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D016392:Proto-Oncogene Proteins pp60(c-src)