Michael Karin

Date: November 18, 2002

The I B kinase (IKK) complex is composed of 3 subunits: IKK, IKK, and IKK. IKK and IKK, the catalytic subunits, display a high degree of biochemical and structural similarity, both functioning as I B kinases in vitro. The physiological function of the different IKK subunits and the reason for duplication of the catalytic subunits was probed by gene disruption and knockin experiments. At their outset, these experiments demonstrated a critical function for IKK in activation of NF- B in response to a large number of proinflammatory stimuli, including TNF, IL-1, dsRNA, LPS and ISS-DNA. IKK is also essential for prevention of TNF induced apoptosis and is indispensable for activation of innate immune responses.

IKK is required for suppressing the apoptosis of TLR4-activated mouse macrophages and is an essential mediator of acute inflammatory response and tissue protection following exposure to certain physical stresses. All of these IKK - specific functions depend on I B phosphorylation and degradation and are mediated through the canonical NF- B activation pathway. By contrast, the biological functions of IKK were found to be rather complex and perplexing. Although IKK was found not to be required for activation of the canonical NF- B pathway in response to proinflammatory stimuli, it is essential for skin and bone morphogenesis.

The role of IKK in epidermal differentiation, however, does not depend on its protein kinase activity nor on NF- B. Recently, IKK was found to have a second function – being required for activation of a second NF- B pathway based on the processing of NF- B2/p100 to p52. This function does depend on the kinase activity of IKK and seems to be triggered only by select members of the TNF family. This function is required for adaptive immune responses and proper organization and development of lymphoid organs.

It appears that the most critical function of IKK in this context is exerted within the B lymphocyte compartment. A third function of IKK that is also dependent on its kinase activity is in development of the mammary gland. This function is exerted via the canonical NF- B pathway (i.e. I B degradation) but is not triggered by standard proinflammatory stimuli. In summary, duplication of the IKK catalytic subunits has enabled the assumption of diverse biological functions that are differentially dependent on IKK and IKK.