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

Science 308 (5718): 114-118

Copyright © 2005 by the American Association for the Advancement of Science

PDK1 Nucleates T Cell Receptor-Induced Signaling Complex for NF-{kappa}B Activation

Ki-Young Lee, Fulvio D'Acquisto, Matthew S. Hayden, Jae-Hyuck Shim, Sankar Ghosh*

Abstract: Activation of the transcription factor NF-{kappa}B after engagement of the T cell receptor (TCR) is important for T cell proliferation and activation during the adaptive immune response. Recent reports have elucidated a signaling pathway that involves the protein kinase C {theta} (PKC{theta}), the scaffold protein CARD11 (also called CARMA-1), the caspase recruitment domain (CARD)–containing protein Bcl10, and the paracaspase (protease related to caspases) MALT1 as critical intermediates linking the TCR to the I{kappa}B kinase (IKK) complex. However, the events proximal to the TCR that initiate the activation of this signaling pathway remain poorly defined. We demonstrate that 3-phosphoinositide-dependent kinase 1 (PDK1) has an essential role in this pathway by regulating the activation of PKC{theta} and through signal-dependent recruiting of both PKC{theta} and CARD11 to lipid rafts. PDK1-associated PKC{theta} recruits the IKK complex, whereas PDK1-associated CARD11 recruits the Bcl10-MALT1 complex, thereby allowing activation of the IKK complex through Bcl10-MALT1–dependent ubiquitination of the IKK complex subunit known as NEMO (NF-{kappa}B essential modifier). Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-{kappa}B activation pathway in T cells.

Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.

* To whom correspondence should be addressed. E-mail: Sankar.ghosh{at}yale.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Phosphoinositide (3,4,5)-Triphosphate Binding to Phosphoinositide-Dependent Kinase 1 Regulates a Protein Kinase B/Akt Signaling Threshold That Dictates T-Cell Migration, Not Proliferation.
C. Waugh, L. Sinclair, D. Finlay, J. R. Bayascas, and D. Cantrell (2009)
Mol. Cell. Biol. 29, 5952-5962
   Abstract »    Full Text »    PDF »
Magnesium Deficiency Causes Loss of Response to Intermittent Hypoxia in Paraganglion Cells.
S. Torii, K. Kobayashi, M. Takahashi, K. Katahira, K. Goryo, N. Matsushita, K.-i. Yasumoto, Y. Fujii-Kuriyama, and K. Sogawa (2009)
J. Biol. Chem. 284, 19077-19089
   Abstract »    Full Text »    PDF »
Modular Design of Immunological Synapses and Kinapses.
M. L. Dustin (2009)
Cold Spring Harb Perspect Biol 1, a002873
   Abstract »    Full Text »    PDF »
A20 Negatively Regulates T Cell Receptor Signaling to NF-{kappa}B by Cleaving Malt1 Ubiquitin Chains.
M. Duwel, V. Welteke, A. Oeckinghaus, M. Baens, B. Kloo, U. Ferch, B. G. Darnay, J. Ruland, P. Marynen, and D. Krappmann (2009)
J. Immunol. 182, 7718-7728
   Abstract »    Full Text »    PDF »
Thymic OX40 Expression Discriminates Cells Undergoing Strong Responses to Selection Ligands.
M. Klinger, J. K. Kim, S. A. Chmura, A. Barczak, D. J. Erle, and N. Killeen (2009)
J. Immunol. 182, 4581-4589
   Abstract »    Full Text »    PDF »
Induction of HIV Transcription by Nef Involves Lck Activation and Protein Kinase C{theta} Raft Recruitment Leading to Activation of ERK1/2 but Not NF{kappa}B.
V. Witte, B. Laffert, P. Gintschel, E. Krautkramer, K. Blume, O. T. Fackler, and A. S. Baur (2008)
J. Immunol. 181, 8425-8432
   Abstract »    Full Text »    PDF »
Signals and Sequences That Control CD28 Localization to the Central Region of the Immunological Synapse.
M. Sanchez-Lockhart, B. Graf, and J. Miller (2008)
J. Immunol. 181, 7639-7648
   Abstract »    Full Text »    PDF »
NK cell-activating receptors require PKC-{theta} for sustained signaling, transcriptional activation, and IFN-{gamma} secretion.
I. Tassi, M. Cella, R. Presti, A. Colucci, S. Gilfillan, D. R. Littman, and M. Colonna (2008)
Blood 112, 4109-4116
   Abstract »    Full Text »    PDF »
The Protein Kinase C-Responsive Inhibitory Domain of CARD11 Functions in NF-{kappa}B Activation To Regulate the Association of Multiple Signaling Cofactors That Differentially Depend on Bcl10 and MALT1 for Association.
R. R. McCully and J. L. Pomerantz (2008)
Mol. Cell. Biol. 28, 5668-5686
   Abstract »    Full Text »    PDF »
Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II: ROLE IN MESANGIAL CELL HYPERTROPHY AND FIBRONECTIN EXPRESSION.
K. Block, A. Eid, K. K. Griendling, D.-Y. Lee, Y. Wittrant, and Y. Gorin (2008)
J. Biol. Chem. 283, 24061-24076
   Abstract »    Full Text »    PDF »
A Critical Role for Protein Kinase C-{theta}-Mediated T Cell Survival in Cardiac Allograft Rejection.
S. Manicassamy, D. Yin, Z. Zhang, L. L. Molinero, M.-L. Alegre, and Z. Sun (2008)
J. Immunol. 181, 513-520
   Abstract »    Full Text »    PDF »
Natural killer cells from protein kinase C {theta}-/- mice stimulated with interleukin-12 are deficient in production of interferon-{gamma}.
K. M. Page, D. Chaudhary, S. J. Goldman, and M. T. Kasaian (2008)
J. Leukoc. Biol. 83, 1267-1276
   Abstract »    Full Text »    PDF »
T-Cell Receptor-Induced NF-{kappa}B Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b.
G. Qiao, Z. Li, L. Molinero, M.-L. Alegre, H. Ying, Z. Sun, J. M. Penninger, and J. Zhang (2008)
Mol. Cell. Biol. 28, 2470-2480
   Abstract »    Full Text »    PDF »
Antigen-induced clustering of surface CD38 and recruitment of intracellular CD38 to the immunologic synapse.
P. Munoz, M. Mittelbrunn, H. de la Fuente, M. Perez-Martinez, A. Garcia-Perez, A. Ariza-Veguillas, F. Malavasi, M. Zubiaur, F. Sanchez-Madrid, and J. Sancho (2008)
Blood 111, 3653-3664
   Abstract »    Full Text »    PDF »
Stromal cell-derived factor 1-{alpha} (SDF)-induced human T cell chemotaxis becomes phosphoinositide 3-kinase (PI3K)-independent: role of PKC-{theta}.
N. A. Shahabi, K. McAllen, and B. M. Sharp (2008)
J. Leukoc. Biol. 83, 663-671
   Abstract »    Full Text »    PDF »
The Tumor Suppressor Death-Associated Protein Kinase Targets to TCR-Stimulated NF-{kappa}B Activation.
Y.-T. Chuang, L.-W. Fang, M.-H. Lin-Feng, R.-H. Chen, and M.-Z. Lai (2008)
J. Immunol. 180, 3238-3249
   Abstract »    Full Text »    PDF »
I{kappa}B kinase induced phosphorylation of CARMA1 contributes to CARMA1 Bcl10 MALT1 complex formation in B cells.
H. Shinohara, S. Maeda, H. Watarai, and T. Kurosaki (2007)
J. Exp. Med. 204, 3285-3293
   Abstract »    Full Text »    PDF »
The TCL1 oncoprotein inhibits activation-induced cell death by impairing PKC{theta} and ERK pathways.
G. Despouy, M. Joiner, E. Le Toriellec, R. Weil, and M. H. Stern (2007)
Blood 110, 4406-4416
   Abstract »    Full Text »    PDF »
Bcl10 Plays a Divergent Role in NK Cell-Mediated Cytotoxicity and Cytokine Generation.
S. Malarkannan, J. Regunathan, H. Chu, S. Kutlesa, Y. Chen, H. Zeng, R. Wen, and D. Wang (2007)
J. Immunol. 179, 3752-3762
   Abstract »    Full Text »    PDF »
Caveolin-1 Triggers T-cell Activation via CD26 in Association with CARMA1.
K. Ohnuma, M. Uchiyama, T. Yamochi, K. Nishibashi, O. Hosono, N. Takahashi, S. Kina, H. Tanaka, X. Lin, N. H. Dang, et al. (2007)
J. Biol. Chem. 282, 10117-10131
   Abstract »    Full Text »    PDF »
Negative feedback loop in T cell activation through I{kappa}B kinase-induced phosphorylation and degradation of Bcl10.
C. Lobry, T. Lopez, A. Israel, and R. Weil (2007)
PNAS 104, 908-913
   Abstract »    Full Text »    PDF »
Regulation and Function of IKK and IKK-Related Kinases.
H. Hacker and M. Karin (2006)
Sci. STKE 2006, re13
   Abstract »    Full Text »    PDF »
Minimal model of spiky oscillations in NF-{kappa}B signaling.
S. Krishna, M. H. Jensen, and K. Sneppen (2006)
PNAS 103, 10840-10845
   Abstract »    Full Text »    PDF »
Phosphoinositide-dependent kinase 1 targets protein kinase A in a pathway that regulates interleukin 4.
A. Nirula, M. Ho, H. Phee, J. Roose, and A. Weiss (2006)
J. Exp. Med. 203, 1733-1744
   Abstract »    Full Text »    PDF »
Ca2+/Calmodulin-Dependent Protein Kinase II Is a Modulator of CARMA1-Mediated NF-{kappa}B Activation..
K. Ishiguro, T. Green, J. Rapley, H. Wachtel, C. Giallourakis, A. Landry, Z. Cao, N. Lu, A. Takafumi, H. Goto, et al. (2006)
Mol. Cell. Biol. 26, 5497-5508
   Abstract »    Full Text »    PDF »
Protein Kinase C-{theta}-Mediated Signals Enhance CD4+ T Cell Survival by Up-Regulating Bcl-xL..
S. Manicassamy, S. Gupta, Z. Huang, and Z. Sun (2006)
J. Immunol. 176, 6709-6716
   Abstract »    Full Text »    PDF »
Phosphorylation of TNF-{alpha} converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation.
Q. Zhang, S. M. Thomas, V. W. Y. Lui, S. Xi, J. M. Siegfried, H. Fan, T. E. Smithgall, G. B. Mills, and J. R. Grandis (2006)
PNAS 103, 6901-6906
   Abstract »    Full Text »    PDF »
POLKADOTS Are Foci of Functional Interactions in T-Cell Receptor-mediated Signaling to NF-{kappa}B.
J. S. Rossman, N. G. Stoicheva, F. D. Langel, G. H. Patterson, J. Lippincott-Schwartz, and B. C. Schaefer (2006)
Mol. Biol. Cell 17, 2166-2176
   Abstract »    Full Text »    PDF »
Engagement of CD28 Outside of the Immunological Synapse Results in Up-Regulation of IL-2 mRNA Stability but Not IL-2 Transcription..
M. Sanchez-Lockhart and J. Miller (2006)
J. Immunol. 176, 4778-4784
   Abstract »    Full Text »    PDF »
TRAF6 activation of PI 3-kinase-dependent cytoskeletal changes is cooperative with Ras and is mediated by an interaction with cytoplasmic Src.
K. Z. Q. Wang, N. Wara-Aswapati, J. A. Boch, Y. Yoshida, C.-D. Hu, D. L. Galson, and P. E. Auron (2006)
J. Cell Sci. 119, 1579-1591
   Abstract »    Full Text »    PDF »
Comment on "PDK1 Nucleates T Cell Receptor-Induced Signaling Complex for NF-{kappa}B Activation".
T. Gruber, M. Freeley, N. Thuille, I. Heit, S. Shaw, A. Long, and G. Baier (2006)
Science 312, 55a
   Abstract »    Full Text »    PDF »
Response to Comment on "PDK1 Nucleates T Cell Receptor-Induced Signaling Complex for NF-{kappa}B Activation".
K.-y. Lee, J.-H. Shim, M. S. Hayden, J.-S. Luehrmann, and S. Ghosh (2006)
Science 312, 55b
   Abstract »    Full Text »    PDF »
The Long-term Survival of a Patient With Pancreatic Cancer With Metastases to the Liver After Treatment With the Intravenous {alpha}-Lipoic Acid/Low-Dose Naltrexone Protocol.
B. M. Berkson, D. M. Rubin, and A. J. Berkson (2006)
Integr Cancer Ther 5, 83-89
   Abstract »    PDF »
CARMA1 Is Required for Akt-Mediated NF-{kappa}B Activation in T Cells..
P. Narayan, B. Holt, R. Tosti, and L. P. Kane (2006)
Mol. Cell. Biol. 26, 2327-2336
   Abstract »    Full Text »    PDF »
Gene Expression Profiles Associated with Treatment Response in Oligodendrogliomas.
P. J. French, S. M.A. Swagemakers, J. H.A. Nagel, M. C.M. Kouwenhoven, E. Brouwer, P. van der Spek, T. M. Luider, J. M. Kros, M. J. van den Bent, and P. A. Sillevis Smitt (2005)
Cancer Res. 65, 11335-11344
   Abstract »    Full Text »    PDF »
3-Phosphoinositide-dependent Protein Kinase-1-mediated I{kappa}B Kinase {beta} (IKKB) Phosphorylation Activates NF-{kappa}B Signaling.
H. Tanaka, N. Fujita, and T. Tsuruo (2005)
J. Biol. Chem. 280, 40965-40973
   Abstract »    Full Text »    PDF »
PKC{beta} regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1.
H. Shinohara, T. Yasuda, Y. Aiba, H. Sanjo, M. Hamadate, H. Watarai, H. Sakurai, and T. Kurosaki (2005)
J. Exp. Med. 202, 1423-1431
   Abstract »    Full Text »    PDF »
IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508.
E. S. Hwang, J.-H. Hong, and L. H. Glimcher (2005)
J. Exp. Med. 202, 1289-1300
   Abstract »    Full Text »    PDF »
The NF-{kappa}B pathway.
P. N. Moynagh (2005)
J. Cell Sci. 118, 4589-4592
   Full Text »    PDF »

To Advertise     Find Products

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