Jorge Moscat and María Diaz-Meco

Fig. 1. The AID sequences of p62 and MEK5 aligned with the corresponding putative region of Par-6. Identical and closely related residues are shown in gray.

Fig. 2. The modulation of aPKC function by different protein complexes. (A) In response to TNFα receptor stimulation, the death domain (DD) of the corresponding receptor binds the adapter TRADD, which serves to recruit RIP. The coiled-coil (CC) region of RIP interacts with the atypical zinc finger (ZZ) of p62. The AID sequence of p62 interacts with the V1 domain of the aPKCs and serves to recruit them to the receptor signaling complex, and to activate them through an unknown mechanism. The inhibitory protein Par-4 can target the zinc finger (ZF) of the aPKCs, provoking their inhibition and the subsequent induction of apoptosis. (B) TRAF6 also interacts with p62, linking the aPKCs to the IL-1 signaling cascade. IRAK, after it is recruited to the IL-1 signaling complex, is hyperphosphorylated and released to interact with TRAF6. The recruitment of IRAK to the IL-1 receptor complex takes place through its interaction with the adapter MyD88, which binds the IL-1 receptor through the TIR domain. IKK can be recruited to these complexes through RIP or the TRAFs where its β subunit can be phosphorylated and activated by the aPKCs. (C) CDC42 or Rac may stimulate Par-6 (AID site), which forms a complex with the aPKCs (V1 site) in close proximity to Par-3, which interacts with the PDZ domain of Par-6. This results in the phosphorylation of Par-3 by the aPKCs, leading to downstream effects on cytoskeletal arrangement. The interaction between Par-6 and CDC42 may explain the role of the aPKCs in cytoskeletal remodeling during Ras transformation, since Ras is known to activate CDC42.