Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex.
Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Indeed, CD40, a tumor necrosis factor receptor (TNFR) family member, forms a complex containing adaptor molecules TRAF2 and TRAF3, ubiquitin-conjugating enzyme Ubc13, cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2), IkappaB kinase regulatory subunit IKKgamma (also called NEMO), and mitogen-activated protein kinase (MAPK) kinase kinase MEKK1 upon ligation. TRAF2, Ubc13, and IKKgamma were required for complex assembly and activation of MEKK1 and MAPK cascades. However, these kinases were not activated unless the multicomponent signaling complex translocated from CD40 to the cytosol upon c-IAP1/2-induced degradation of TRAF3. This two-stage signaling mechanism may apply to other innate immune receptors, accounting for spatial and temporal separation of MAPK and IKK signaling.
Matsuzawa
Atsushi
A
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
Tseng
Ping-Hui
PH
Vallabhapurapu
Sivakumar
S
Luo
Jun-Li
JL
Zhang
Weizhou
W
Wang
Haopeng
H
Vignali
Dario A A
DA
Gallagher
Ewen
E
Karin
Michael
M
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004789:Enzyme Activation; D051550:I-kappa B Kinase / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
D019013:CD40 Antigens; D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D046988:Proteasome Endopeptidase Complex; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D044763:Ubiquitin-Conjugating Enzymes; D000099151:MAP Kinase Kinase Kinase 7; C514982:Ube2n protein, mouse