PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation

TY - JOUR

T1 - PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation

AU - Lee, Ki-Young

AU - D'Acquisto, Fulvio

AU - Hayden, Matthew S

AU - Shim, Jae-Hyuck

AU - Ghosh, Sankar

PY - 2005/4/1

Y1 - 2005/4/1

N2 - Activation of the transcription factor NF-kappaB 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 (PKC), 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 IkappaB 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 and through signal-dependent recruiting of both PKC and CARD11 to lipid rafts. PDK1-associated PKC 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-kappaB essential modifier). Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-kappaB activation pathway in T cells.

AB - Activation of the transcription factor NF-kappaB 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 (PKC), 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 IkappaB 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 and through signal-dependent recruiting of both PKC and CARD11 to lipid rafts. PDK1-associated PKC 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-kappaB essential modifier). Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-kappaB activation pathway in T cells.

KW - 3-Phosphoinositide-Dependent Protein Kinases

KW - Adaptor Proteins, Signal Transducing

KW - Apoptosis Regulatory Proteins

KW - B-Cell CLL-Lymphoma 10 Protein

KW - CARD Signaling Adaptor Proteins

KW - Carrier Proteins

KW - Caspases

KW - Cell Line

KW - Cell Line, Tumor

KW - Enzyme Activation

KW - Guanylate Cyclase

KW - Humans

KW - I-kappa B Kinase

KW - Isoenzymes

KW - Jurkat Cells

KW - Lymphocyte Activation

KW - Lymphoma, B-Cell, Marginal Zone

KW - Membrane Microdomains

KW - Membrane Proteins

KW - Models, Biological

KW - Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

KW - NF-kappa B

KW - Neoplasm Proteins

KW - Phosphatidylinositol 3-Kinases

KW - Phosphorylation

KW - Protein Kinase C

KW - Protein Kinase C-theta

KW - Protein-Serine-Threonine Kinases

KW - RNA Interference

KW - Receptors, Antigen, T-Cell

KW - Signal Transduction

KW - T-Lymphocytes

KW - Transfection

KW - Journal Article

KW - Research Support, U.S. Gov't, P.H.S.

U2 - 10.1126/science.1107107

DO - 10.1126/science.1107107

M3 - Article

C2 - 15802604

SN - 0036-8075

VL - 308

SP - 114

EP - 118

JO - SCIENCE

JF - SCIENCE

IS - 5718

ER -