Protein kinase C-associated kinase (PKK) mediates Bcl10-independent NF-κB activation induced by phorbol ester

Abstract

Protein kinase C-associated kinase (PKK) is a recently described kinase of unknown function that was identified on the basis of its specific interaction with PKCβ. PKK contains N-terminal kinase and C-terminal ankyrin repeats domains linked to an intermediate region. Here we report that the kinase domain of PKK is highly homologous to that of two mediators of nuclear factor-κB (NF-κB) activation, RICK and RIP, but these related kinases have different C-terminal domains for binding to upstream factors. We find that expression of PKK, like RICK and RIP, induces NF-κB activation. Mutational analysis revealed that the kinase domain of PKK is essential for NF-κB activation, whereas replacement of serine residues in the putative activation loop did not affect the ability of PKK to activate NF-κB. A catalytic inactive PKK mutant inhibited NF-κB activation induced by phorbol ester and Ca2+-ionophore, but it did not block that mediated by tumor necrosis factor a, interleukin-1β, or Nod1. Inhibition of NF-κB activation by dominant negative PKK was reverted by co-expression of PKCβI, suggesting a functional association between PKK and PKCβI. PKK-mediated NF-κB activation required IKKα and IKKβ but not IKKγ, the regulatory subunit of the IKK complex. Moreover, NF-κB activation induced by PKK was not inhibited by dominant negative Bimpl and proceeded in the absence of Bcl10, two components of a recently described PKC signaling pathway. These results suggest that PKK is a member of the RICK/RIP family of kinases, which is involved in a PKC-activated NF-κB signaling pathway that is independent of Bcl10 and IKKγ.