Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 104 (1): 145-150

Copyright © 2007 by the National Academy of Sciences.


Bcl10 plays a critical role in NF-{kappa}B activation induced by G protein-coupled receptors

Donghai Wang*,{dagger}, Yun You*, Pei-Chun Lin*, Liquan Xue{ddagger}, Stephan W. Morris{ddagger}, Hu Zeng§, Renren Wen§, and Xin Lin*

*Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; {ddagger}Departments of Pathology and Hematology–Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105; and §Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53201

Edited by Michael Karin, University of California at San Diego School of Medicine, La Jolla, CA, and approved November 14, 2006

Received for publication March 9, 2006.

Abstract: G protein-coupled receptors (GPCRs) play pivotal roles in cell proliferation, differentiation, and survival. Although many studies indicate that the stimulation of GPCRs leads to NF-{kappa}B activation, the molecular mechanism by which GPCRs induced NF-{kappa}B activation remains largely unknown. Bcl10 is an essential adaptor molecule connecting antigen receptor signaling cascades to NF-{kappa}B activation in lymphocytes. However, the function of Bcl10 in nonlymphoid cells remains to be determined. In this study, we demonstrated that the deficiency of Bcl10 resulted in the defect in NF-{kappa}B activation induced by either expressing the constitutively active mutant of G protein or stimulation of cells with lysophosphatidic acid or endothelin-1, which activate their GPCR. In contrast, TNF-{alpha}-, LPS-, and integrin-induced NF-{kappa}B activation was not affected in Bcl10-deficient cells. Together, our results provide genetic evidence showing that Bcl10 is a key signaling component mediating NF-{kappa}B activation induced by GPCRs in nonlymphoid cells.

Key Words: lysophosphatidic acid • signal transduction • endothelin-1

Author contributions: D.W. and Y.Y. contributed equally to this work; D.W. and X.L. designed research; D.W., Y.Y., P.-C.L., H.Z., and R.W. performed research; L.X. and S.W.M. contributed new reagents/analytic tools; D.W., Y.Y., P.-C.L., H.Z., R.W., and X.L. analyzed data; and D.W. and X.L. wrote the paper.

{dagger}Present address: The CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

This article contains supporting information online at

To whom correspondence should be addressed. E-mail: xllin{at}

© 2007 by The National Academy of Sciences of the USA

Forkhead Transcription Factor FOXO3a Protein Activates Nuclear Factor {kappa}B through B-cell lymphoma/leukemia 10 (BCL10) Protein and Promotes Tumor Cell Survival in Serum Deprivation.
Z. Li, H. Zhang, Y. Chen, L. Fan, and J. Fang (2012)
J. Biol. Chem. 287, 17737-17745
   Abstract »    Full Text »    PDF »
The E3 Ubiquitin Ligase Mind Bomb-2 (MIB2) Protein Controls B-cell CLL/Lymphoma 10 (BCL10)-dependent NF-{kappa}B Activation.
C. C. Stempin, L. Chi, J. P. Giraldo-Vela, A. A. High, H. Hacker, and V. Redecke (2011)
J. Biol. Chem. 286, 37147-37157
   Abstract »    Full Text »    PDF »
Specific effects of BCL10 Serine mutations on phosphorylations in canonical and noncanonical pathways of NF-{kappa}B activation following carrageenan.
S. Bhattacharyya, A. Borthakur, A. N. Anbazhagan, S. Katyal, P. K. Dudeja, and J. K. Tobacman (2011)
Am J Physiol Gastrointest Liver Physiol 301, G475-G486
   Abstract »    Full Text »    PDF »
CARMA3 is Crucial for EGFR-Induced Activation of NF-{kappa}B and Tumor Progression.
T. Jiang, B. Grabiner, Y. Zhu, C. Jiang, H. Li, Y. You, J. Lang, M.-C. Hung, and X. Lin (2011)
Cancer Res. 71, 2183-2192
   Abstract »    Full Text »    PDF »
Thrombin-dependent NF-{kappa}B Activation and Monocyte/Endothelial Adhesion Are Mediated by the CARMA3{middle dot}Bcl10{middle dot}MALT1 Signalosome.
P. C. Delekta, I. J. Apel, S. Gu, K. Siu, Y. Hattori, L. M. McAllister-Lucas, and P. C. Lucas (2010)
J. Biol. Chem. 285, 41432-41442
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor Receptor-associated Factor-6 and Ribosomal S6 Kinase Intracellular Pathways Link the Angiotensin II AT1 Receptor to the Phosphorylation and Activation of the I{kappa}B Kinase Complex in Vascular Smooth Muscle Cells.
P. Doyon and M. J. Servant (2010)
J. Biol. Chem. 285, 30708-30718
   Abstract »    Full Text »    PDF »
Protein Phosphatase 2A Acts as a Mitogen-activated Protein Kinase Kinase Kinase 3 (MEKK3) Phosphatase to Inhibit Lysophosphatidic Acid-induced I{kappa}B Kinase {beta}/Nuclear Factor-{kappa}B Activation.
W. Sun, H. Wang, X. Zhao, Y. Yu, Y. Fan, H. Wang, X. Wang, X. Lu, G. Zhang, S. Fu, et al. (2010)
J. Biol. Chem. 285, 21341-21348
   Abstract »    Full Text »    PDF »
Phosphorylation of Thr-516 and Ser-520 in the Kinase Activation Loop of MEKK3 Is Required for Lysophosphatidic Acid-mediated Optimal I{kappa}B Kinase {beta} (IKK{beta})/Nuclear Factor-{kappa}B (NF-{kappa}B) Activation.
W. Sun, N. Ge, Y. Yu, S. Burlingame, X. Li, M. Zhang, S. Ye, S. Fu, and J. Yang (2010)
J. Biol. Chem. 285, 7911-7918
   Abstract »    Full Text »    PDF »
B-cell CLL/Lymphoma 10 (BCL10) Is Required for NF-{kappa}B Production by Both Canonical and Noncanonical Pathways and for NF-{kappa}B-inducing Kinase (NIK) Phosphorylation.
S. Bhattacharyya, A. Borthakur, S. Tyagi, R. Gill, M. L. Chen, P. K. Dudeja, and J. K. Tobacman (2010)
J. Biol. Chem. 285, 522-530
   Abstract »    Full Text »    PDF »
{beta}-Arrestin 2 is required for lysophosphatidic acid-induced NF-{kappa}B activation.
J. Sun and X. Lin (2008)
PNAS 105, 17085-17090
   Abstract »    Full Text »    PDF »
Lipopolysaccharide activates NF-{kappa}B by TLR4-Bcl10-dependent and independent pathways in colonic epithelial cells.
S. Bhattacharyya, P. K. Dudeja, and J. K. Tobacman (2008)
Am J Physiol Gastrointest Liver Physiol 295, G784-G790
   Abstract »    Full Text »    PDF »
Transcriptional and post-transcriptional mechanisms for lysophosphatidic acid-induced cyclooxygenase-2 expression in ovarian cancer cells.
R. A. Oyesanya, Z. P. Lee, J. Wu, J. Chen, Y. Song, A. Mukherjee, P. Dent, T. Kordula, H. Zhou, and X. Fang (2008)
FASEB J 22, 2639-2651
   Abstract »    Full Text »    PDF »
A20 is a negative regulator of BCL10- and CARMA3-mediated activation of NF-{kappa}B.
R. Stilo, E. Varricchio, D. Liguoro, A. Leonardi, and P. Vito (2008)
J. Cell Sci. 121, 1165-1171
   Abstract »    Full Text »    PDF »
Malt1 ubiquitination triggers NF-{kappa}B signaling upon T-cell activation.
A. Oeckinghaus, E. Wegener, V. Welteke, U. Ferch, S. C. Arslan, J. Ruland, C. Scheidereit, and D. Krappmann (2007)
EMBO J. 26, 4634-4645
   Abstract »    Full Text »    PDF »
Bcl10 mediates LPS-induced activation of NF-{kappa}B and IL-8 in human intestinal epithelial cells.
S. Bhattacharyya, A. Borthakur, N. Pant, P. K. Dudeja, and J. K. Tobacman (2007)
Am J Physiol Gastrointest Liver Physiol 293, G429-G437
   Abstract »    Full Text »    PDF »
CARD-Bcl10-Malt1 Signalosomes: Missing Link to NF-{kappa}B.
E. Wegener and D. Krappmann (2007)
Sci. STKE 2007, pe21
   Abstract »    Full Text »    PDF »
CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-{kappa}B activation.
B. C. Grabiner, M. Blonska, P.-C. Lin, Y. You, D. Wang, J. Sun, B. G. Darnay, C. Dong, and X. Lin (2007)
Genes & Dev. 21, 984-996
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882