Heterogeneity in the Phosphorylation of Human Death Receptors by p42mapk/erk2

Abstract

Phosphorylation of murine CD120a by p42mapk/erk2 has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-κB activation. Therefore, we sought to determine if p42mapk/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 p42mapk/erk2 but Fas, DR4 and DR5 are not. Additionally, we demonstrated that (i) the p42mapk/erk2-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42mapk/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 p42mapk/erk2-dependent phosphorylation of the DR3 cytoplasmic domain occurred exclusively at non-p42/44mapk/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 p42mapk/erk2.