p62 at the crossroads of autophagy, apoptosis, and cancer

Abstract

The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor NF-kappaB. Recent findings link p62 activity to the extrinsic apoptosis pathway, and Mathew et al. (2009) now show that the modulation of p62 by autophagy is a key factor in tumorigenesis. These findings place p62 at critical decision points that control cell death and survival.

Figure 1. Cellular Functions of p62

(A) Structural domain organization of p62 and p62-interacting partners. p62 has a PB1 domain, a ZZ-type zinc finger domain, a TRAF6-binding (TB) domain, an LC3-interacting region (LIR), and a ubiquitin-associated domain (UBA). (B) p62 speckles promote the oligomerization of TRAF6 and caspase-8 leading to the enhancement of NF-κB activation and apoptosis, respectively. p62 speckles also sequester active ERK, restraining adipogenesis. (C) Autophagy deficiency in apoptosis-impaired tumor cells leads to increased p62 aggregation. This triggers a positive feedback loop for the generation of reactive oxygen species (ROS) and enhanced genomic instability and tumorigenesis. (D) Ras-induced transformation promotes the accumulation of p62, which leads to an increase in NF-κB activity, thereby restraining ROS production and inhibiting tumor cell death. DISC, death-inducing signaling complex; ER, endoplasmic reticulum.