title: Akt-phosphorylated mitogen-activated kinase-activating death domain protein (MADD) inhibits TRAIL-induced apoptosis by blocking Fas-associated death domain (FADD) association with death receptor 4.
abstract: MADD plays an essential role in cancer cell survival. Abrogation of endogenous MADD expression results in significant spontaneous apoptosis and enhanced susceptibility to tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. However, the regulation of MADD function is largely unknown. Here, we demonstrate that endogenous MADD is phosphorylated at three highly conserved sites by Akt, and only the phosphorylated MADD can directly interact with the TRAIL receptor DR4 thereby preventing Fas-associated death domain recruitment. However, in cells susceptible to TRAIL treatment, TRAIL induces a reduction in MADD phosphorylation levels resulting in MADD dissociation from, and Fas-associated death domain association with DR4, which allows death-inducing signaling complex (DISC) formation leading to apoptosis. Thus, the pro-survival function of MADD is dependent upon its phosphorylation by Akt. Because Akt is active in most cancer cells and phosphorylated MADD confers resistance to TRAIL-induced apoptosis, co-targeting Akt-MADD axis is likely to increase efficacy of TRAIL-based therapies.
authors.affiliation: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Peifeng
authors.initials: P
authors.lastname: Li
authors.forename: Shankar
authors.initials: S
authors.lastname: Jayarama
authors.forename: Lakshmy
authors.initials: L
authors.lastname: Ganesh
authors.forename: David
authors.initials: D
authors.lastname: Mordi
authors.forename: Ryan
authors.initials: R
authors.lastname: Carr
authors.forename: Prasad
authors.initials: P
authors.lastname: Kanteti
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013194:Staining and Labeling; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D020662:Guanine Nucleotide Exchange Factors; C105852:MADD protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D051057:Proto-Oncogene Proteins c-akt