title: Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma.
abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-κB pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-κB pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-κB activation through recruiting G protein subunits Gαi and Gα12 to activate PKCβ/CARMA1/TRAF6/NEMO signaling axis followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO. Moreover, functional inhibition of SMO enhances the cytotoxic effects of NF-κB inhibitor. Altogether, our study reveals a noncanonical Hh signaling pathway in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-κB activation. This signaling cascade contributes to the survival of DLBCL and may serve as a potential target for combination therapies in DLBCL.
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Changju
authors: C
authors: Qu
authors: Yadong
authors: Y
authors: Liu
authors: Kranthi
authors: K
authors: Kunkalla
authors: Rajesh R
authors: RR
authors: Singh
authors: Marzenna
authors: M
authors: Blonska
authors: Xin
authors: X
authors: Lin
authors: Nitin Kumar
authors: NK
authors: Agarwal
authors: Francisco
authors: F
authors: Vega
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D017209:Apoptosis; D000074018:B-Cell CLL-Lymphoma 10 Protein; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D064546:Protein Kinase C beta; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000072086:Smoothened Receptor; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D053823:Hedgehog Proteins; C491731:IKBKG protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D048029:TNF Receptor-Associated Factor 6; D008156:Luciferases; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D020962:Heterotrimeric GTP-Binding Proteins; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
references: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17085-90
references: 18952848
references: J Immunol. 1999 Mar 1;162(5):2655-62
references: 10072508
references: Genes Dev. 2007 Apr 15;21(8):984-96
references: 17438001
references: Annu Rev Biochem. 1987;56:615-49
references: 3113327
references: Immunity. 2006 Jun;24(6):729-739
references: 16782029
references: Immunity. 2005 Dec;23(6):561-74
references: 16356855
references: Mod Pathol. 2009 Oct;22(10):1312-20
references: 19593328
references: Nature. 2006 May 4;441(7089):106-10
references: 16572121
references: Science. 1996 Aug 9;273(5276):788-91
references: 8670417
references: J Immunol. 1998 Mar 15;160(6):3038-45
references: 9510209
references: Cell Res. 2011 Jan;21(1):55-70
references: 21187856
references: J Biol Chem. 1999 Oct 22;274(43):30353-6
references: 10521409
references: Immunity. 2005 Dec;23(6):575-85
references: 16356856
references: Nature. 2001 May 17;411(6835):349-54
references: 11357142
references: Oncogene. 2011 Dec 8;30(49):4874-86
references: 21625222
references: Nature. 2008 Dec 18;456(7224):967-70
references: 18987629
references: J Biol Chem. 2004 Dec 31;279(53):55633-43
references: 15489227
references: Cancer Res. 2009 Jul 15;69(14):5927-35
references: 19549902
references: Nat Cell Biol. 2012 May 20;14(7):686-96
references: 22609986
references: Stem Cells. 2007 Dec;25(12):3069-80
references: 17901397
references: Mol Cell. 2004 May 7;14(3):289-301
references: 15125833
references: Nature. 1998 Apr 9;392(6676):615-8
references: 9560159
references: Nature. 2004 Jan 8;427(6970):167-71
references: 14695475
references: Methods. 2001 Dec;25(4):383-5
references: 11846607
references: J Exp Med. 2001 Dec 17;194(12):1861-74
references: 11748286
references: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13520-5
references: 18765795
references: Nat Genet. 2011 Jul 31;43(9):830-7
references: 21804550
references: Trends Pharmacol Sci. 2001 Jul;22(7):368-76
references: 11431032
references: Nature. 2009 Jun 4;459(7247):717-21
references: 19412164
references: Mol Cell Biol. 2004 Dec;24(24):10757-65
references: 15572679
references: Leukemia. 2010 May;24(5):1025-36
references: 20200556
references: Cancer Res. 2006 Jul 15;66(14):7041-9
references: 16849549
references: Blood. 2011 Jan 6;117(1):200-10
references: 20889926
references: Cell. 2000 Oct 27;103(3):371-4
references: 11081624
references: J Exp Med. 2007 Dec 24;204(13):3285-93
references: 18086859
references: Annu Rev Immunol. 2000;18:621-63
references: 10837071
references: Nat Immunol. 2002 Sep;3(9):830-5
references: 12154356
references: Cell. 1995 Jun 30;81(7):1159-70
references: 7600583
references: Cancer Res. 2009 Mar 15;69(6):2550-8
references: 19244133
references: J Biochem. 1999 Aug;126(2):340-6
references: 10423527
references: Curr Opin Genet Dev. 1998 Aug;8(4):450-6
references: 9729722
references: Nature. 2002 Aug 22;418(6900):892-7
references: 12192414
references: FASEB J. 2009 Jan;23(1):21-33
references: 18772349
references: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12607-12
references: 16885213
references: Annu Rev Immunol. 1996;14:649-83
references: 8717528
references: Blood. 2004 Jan 1;103(1):275-82
references: 14504078
references: Mol Cell. 2001 Oct;8(4):771-80
references: 11684013
references: Bibl Haematol. 1975 Oct;(43):406-8
references: 183709
references: Curr Top Dev Biol. 2003;53:1-114
references: 12509125
references: Genes Cells. 2004 Jan;9(1):49-58
references: 14723707