IKKα, a critical regulator of epidermal differentiation and a suppressor of skin cancer

I kappa B kinase alpha (IKK alpha), one of the two catalytic subunits of the IKK complex involved in nuclear factor kappa B (NF-kappa B) activation, also functions as a molecular switch that controls epidermal differentiation. This unexpected function requires IKK alpha nuclear translocation but does not depend on its kinase activity, and is independent of NF-kappa B signalling. Ikk alpha(-/-) mice present with a hyperproliferative and undifferentiated epidermis characterized by complete absence of a granular layer and stratum corneum. Ikk alpha-deficient keratinocytes do not express terminal differentiation markers and continue to proliferate even when subjected to differentiation-inducing stimuli. This antiproliferative function of IKK alpha is also important for the suppression of squamous cell carcinogenesis. The exact mechanisms by which nuclear IKK alpha controls keratinocyte proliferation and differentiation remained mysterious for some time. Recent studies, however, have revealed that IKK alpha is a major cofactor in a TGF beta-Smad2/3 signalling pathway that is Smad4 independent. This pathway controls cell cycle withdrawal during keratinocyte terminal differentiation. Although these are not the only functions of nuclear IKK alpha, this multifunctional protein is a key regulator of keratinocyte and epidermal differentiation and a critical suppressor of skin cancer.