IKK alpha controls formation of the epidermis independently of NF-kappa B

The IKK alpha and IKK beta catalytic subunits of I kappaB kinase (IKK) shar e 51% amino-acid identity and similar biochemical activities: they both pho sphorylate I kappaB proteins at serines that trigger their degradation(1-4) . IKK alpha and IKK beta differ, however, in their physiological functions. IKK beta and the IKK gamma /NEMO regulatory subunit are required for activ ating NF-kappaB by pro-inflammatory stimuli and preventing apoptosis induce d by tumour necrosis factor-alpha (refs 5-11). IKK alpha is dispensable for these functions, but is essential for developing the epidermis and its der ivatives(12-15). The mammalian epidermis is composed of the basal, spinous, granular and cornified layers(16). Only basal keratinocytes can proliferat e and give rise to differentiated derivatives, which on full maturation und ergo enucleation to generate the cornified layer. Curiously, keratinocyte-s pecific inhibition of NF-kappaB, as in Ikk alpha (-/-) mice(12-15), results in epidermal thickening but does not block terminal differentiation(17,18) . It has been proposed(19,20) that the epidermal defect in Ikk alpha (-/-) mice may be due to the failed activation of NF-kappaB. Here we show that th e unique function of IKK alpha in control of keratinocyte differentiation i s not exerted through its I kappaB kinase activity or through NF-kappaB. In stead, IKK alpha controls production of a soluble factor that induces kerat inocyte differentiation.