title: Loss of TRB3 alters dynamics of MLK3-JNK signaling and inhibits cytokine-activated pancreatic beta cell death.
abstract: Disabling cellular defense mechanisms is essential for induction of apoptosis. We have previously shown that cytokine-mediated activation of the MAP3K MLK3 stabilizes TRB3 protein levels to inhibit AKT and compromise beta cell survival. Here, we show that genetic deletion of TRB3 results in basal activation of AKT, preserves mitochondrial integrity, and confers resistance against cytokine-induced pancreatic beta cell death. Mechanistically, we find that TRB3 stabilizes MLK3, most likely by suppressing AKT-directed phosphorylation, ubiquitination, and proteasomal degradation of MLK3. Accordingly, TRB3(-/-) islets show a decrease in both the amplitude and duration of cytokine-stimulated MLK3 induction and JNK activation. It is well known that JNK signaling is facilitated by a feed forward loop of sequential kinase phosphorylation and is reinforced by a mutual stabilization of the module components. The failure of TRB3(-/-) islets to mount an optimal JNK activation response, coupled with the ability of TRB3 to engage and maintain steady state levels of MLK3, recasts TRB3 as an integral functional component of the JNK module in pancreatic beta cells.
authors.affiliation: From the Pediatric Diabetes Research Center, University of California, San Diego School of Medicine, La Jolla, California 92037.
authors.forename: Rohan K
authors.initials: RK
authors.lastname: Humphrey
authors.affiliation: From the Pediatric Diabetes Research Center, University of California, San Diego School of Medicine, La Jolla, California 92037.
authors.forename: Anamika
authors.initials: A
authors.lastname: Ray
authors.affiliation: From the Pediatric Diabetes Research Center, University of California, San Diego School of Medicine, La Jolla, California 92037.
authors.forename: Sumati
authors.initials: S
authors.lastname: Gonuguntla
authors.affiliation: From the Pediatric Diabetes Research Center, University of California, San Diego School of Medicine, La Jolla, California 92037.
authors.forename: Ergeng
authors.initials: E
authors.lastname: Hao
authors.affiliation: From the Pediatric Diabetes Research Center, University of California, San Diego School of Medicine, La Jolla, California 92037 ujhala@ucsd.edu.
authors.forename: Ulupi S
authors.initials: US
authors.lastname: Jhala
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D010769:Phosphothreonine; D025821:Polyubiquitin; D051057:Proto-Oncogene Proteins c-akt; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C474830:TRB3 protein, mouse
keywords: Akt PKB; Diabetes; IL-1β; JNK Module; Pancreatic Islet; Protein Degradation; Protein Phosphorylation; Ubiquitination