Signaling control and specificity in cancer: The PB1 paradigm 

The complex signaling network that governs whether cells grow, senesce, or die is highly elaborated but achieves a remarkable degree of specificity due to the existence of adaptors molecules. One such adaptor is the protein called p62 (encoded by the gene SQSTM1). p62/SQSTM1 was discovered in our laboratories initially as an interacting partner of the atypical protein kinase C (aPKC) family, which is composed of two members: PKCz and PKCl/i. Later studies have unveiled the role of p62/SQSTM1 as a substrate of autophagy, serving two purposes. On the one hand, acting as a chaperone targeting misfolded proteins and damaged organelles for degradation through the autophagosome-lysosome system, p62 plays a central role in detoxification and cell quality control. On the other hand, the lysosome-mediated degradation of p62 serves to keep p62 levels under homeostatic control to maintain the signaling cascades dependent on p62 at acceptable thresholds, which helps to prevent excessive cell proliferation.

The structure of p62 accounts for its rich number of interacting partners, which makes p62 a focal point in signal transduction specificity. One of the main featured characteristics of p62’s structure is the N-terminal PB1 domain, which is a protein-protein interaction module found in other signaling molecules such as NBR1, and the kinases PKCz, PKCl/i, MEKK3, and the polarity adaptor Par-6. The combinatorial set of interactions governed by the PB1 domain confers specificity to many signaling events regulating critical functions in normal and cancer cells.

As a paradigmatic example, we have recently unveiled the role that the p62-PKCl/i interaction plays in controlling cell proliferation in liver cancer. We demonstrated that PKCl/i is a tumor suppressor in part because, in a complex with p62, it phosphorylates and inhibits LC3, which is a critical component of the autophagy machinery. This explains why the loss of PKCl/i in hepatocytes results in the upregulation of autophagy, which provides fuel for oxidative phosphorylation and promotes detoxification from the excessive production of radical oxygen species, enhancing cell growth and preventing cell death through the master transcription factor NRF2. All this combined leads to augmented tumorigenicity, a hallmark of the loss of the aPKCs function, common in many types of cancers.