Heterogeneity in the phosphorylation of human death receptors by p42(mapk/erk2).
Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation. Therefore, we sought to determine if p42(mapk/erk2) was also capable of phosphorylating additional human death receptors within the TNF receptor superfamily. These studies showed that CD120a and DR3 are significantly phosphorylated by p42(mapk/erk2) but Fas, DR4 and DR5 are not. Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a, and (iv) the p42(mapk/erk2)-dependent phosphorylation of the DR3 cytoplasmic domain occurred exclusively at non-p42/44(mapk/erk2/1) consensus sites. These findings suggest that human death receptors segregate into two groups along lines of phylogeny with respect to Ser/Thr phosphorylation by p42(mapk/erk2).
Frankel
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SK
Program in Cell Biology, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
Van Linden
A A
AA
Riches
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DW
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D019556:COS Cells; D016384:Consensus Sequence; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D019606:Phosphoamino Acids / Q000032:analysis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D015703:Antigens, CD; D019606:Phosphoamino Acids; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C506033:TNFRSF25 protein, human; D019014:fas Receptor; D019319:Okadaic Acid; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate