Receptor–Induced Signaling Complex for NF-kB Activation

Activation of the transcription factor NF-kB 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 q (PKCq), 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 inter-mediates linking the TCR to the IkB 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 PKCq and through signal-dependent recruiting of both PKCq and CARD11 to lipid rafts. PDK1-associated PKCq 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-kB essential modifier). Hence, PDK1 plays a critica