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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

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