Putative function of PKD2 in NF-κB signaling, based on observations with inactive PKD2. Upon exposure to oxidative stress, a kinase complex comprising dimeric PKD1/2, Src, Abl, and PKCδ is assembled on the outer mitochondrial membrane. In a WT PKD1/2 dimer, the upstream kinases phosphorylate PKD1/2, which causes loss of affinity and consequentially the release of upstream kinases. PKD1 and PKD2 are both activated, but only PKD1 signals to NF-κB. When PKD2 cannot be phosphorylated because of mutations, the upstream kinases retain their affinity for PKD2 and can keep PKD1 phosphorylated (since they will have a similar affinity for PKD1 when it is dephosphorylated). In conjunction with this, the inactive conformation of PKD2, resulting from the fact that it cannot be phosphorylated, could protect PKD1 from phosphatase action. Both these phenomena could explain the enhanced NF-κB signaling output seen with inactive PKD2 mutants. Tyr phosphorylation sites are indicated with yellow-coloured circles, and Ser phosphorylation sites are indicated with red-coloured circles.