The IL-1 receptor accessory protein is essential for PI 3-kinase recruitment and activation.
Interleukin-1 (IL-1) binds to its type I receptors (IL-1R), which in complex with IL-1R accessory protein (IL-1R AcP) induces various intracellular signaling events. We report here that IL-1 triggers the recruitment of phosphoinositide 3-kinase (PI 3-kinase) to a signaling complex and induces its lipid kinase activity in a biphasic manner. This IL-1-induced complex consists of IL-1R, IL-1R AcP, PI 3-kinase, and the IL-1-receptor-associated kinase (IRAK). Deletion of the C-terminus 27 amino acids of IL-1R AcP resulted in a mutant, CDelta27, that could not recruit PI 3-kinase to the signalsome nor stimulate PI3-kinase activity. Moreover, CDelta27 functioned as a dominant-negative mutant that inhibited IL-1-induced PI 3-kinase and NFkappaB activation. CDelta27, however, had no effect on IL-1-dependent activation of the Jun N-terminal kinase (JNK), indicating that distinct regions of IL-1R AcP mediate the activation of PI 3-kinase and JNK. Thus, our results identified a functional region in the IL-1R AcP required for the recruitment and activation of PI 3-kinase.
Reddy
Shrikanth A G
SA
Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Lin
Yu-Feng
YF
Huang
Helen J
HJ
Samanta
Ajoy K
AK
Liao
Warren S-L
WS
D002277:Carcinoma / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D053727:Interleukin-18 Receptor alpha Subunit; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D053724:Receptors, Interleukin-18; D015398:Signal Transduction; D013329:Structure-Activity Relationship
C508572:IL18R1 protein, human; D053727:Interleukin-18 Receptor alpha Subunit; D009097:Multienzyme Complexes; D011506:Proteins; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D053724:Receptors, Interleukin-18; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases