Abstract

Death receptors (DRs) are a subset of the tumor necrosis factor receptor (TNFR) superfamily with a protein interaction motif called the death domain. DRs, particularly TNFR1, FAS and TRAIL-Rs, mediate critical cellular outcomes, including apoptosis, necroptosis, inflammation, survival, and proliferation. Phosphorylation is a rapid, reversible post-translational modification, and therefore might alter the downstream fate decisions in signal transduction pathways. Like most cytokines, death ligands activate a wide range of tyrosine kinases. However, our understanding of whether these tyrosine kinases phosphorylate DRs and modulate downstream signaling is limited. Depending on the cell type, several different tyrosine kinases, including Src family members, JAKs and EGFR have been demonstrated to be activated upon death ligand exposure. All three of these kinase families have the potential to phosphorylate DRs, as reviewed here, and these phosphorylation events create a bias towards proinflammatory and proliferative pathways over cell death. Since these kinases are frequently hyperactivated in cancer, this bias may sustain tumor cell survival and resistance to death receptor–targeted therapies, marking the responsible kinases and their opposing phosphatases as candidate therapeutic targets.