UCSD Signaling Systems Laboratory

Research Interests

The Inhibitor of kappaB Kinase (IKK) is an enzyme complex activated by signaling molecules related to a large number of cellular receptors, including TLR, TNFR, and immune cell receptor families. The complex is composed up of two catalytic subunits, IKKalpha and IKKbeta, as well as the non-catalytic inhibitory subunit NEMO (IKKgamma). IKK serves as the signaling hub for the NF-kappaB pathway, receiving numerous and diverse signals from cellular receptors and activating NF-kappaB to bring about dynamic, signal-specific gene regulation. However, recent data suggests that the regulation of IKK differs from the canonical on/off switch model seen in many kinases, such as the MAPK family.

Activation of the IKK complex results from the phosphorylation of serines in the activation loop of IKKbeta. Studies have shown that upstream kinases (such as TAK1), polyubiquitin scaffold chains, and oligmerization all play a role in the activation of IKK. Deactivation of the enzyme complex is brought about by the dephosphorylation of the IKKbeta active loop serines as well as possible phosphorylation of serines in the C-terminal tail of NEMO by IKKbeta. The protein phosphatase 2A (PP2A) has been implicated in dephosphorylating IKKbeta, while the heat shock protein Hsp90 and its chaperone Cdc37 have been shown to interact with newly synthesized IKK and post-activated IKK; this suggests that PP2A and Hsp90 may be involved in regenerating post-deactivated IKK complex back to a poised state where it can be reactivated. Sustained IKK activity can lead to the chronic NF-kappaB activity found in certain disease states, while elevated levels of constitutive IKK activity have been shown in some tumor lines. Therefore, it is essential to understand the mechanisms by which IKK is regulated and what differs in the regulation of healthy cells and the misregulation of disease state cells in order to develop therapeutics that could potentially direct a disease state cell back to a healthy state. Building on previous research, we have proposed a five-state, cyclic model for the regulation of IKK. In my research I seek to understand how these various effectors regulate IKK activity.