The Emerging Role of Non-traditional Ubiquitination in Oncogenic Pathways

Abstract

The addition of ubiquitin to a target protein has long been implicated in the process of degradation and is the primary mediator of protein turnover in the cell. Recently, however, many non-proteolytic functions of ubiquitination have emerged as key regulators of cellular homeostasis. In this review, we will describe the various non-traditional functions of ubiquitination, with particular focus on how they can be used as signaling entities in cancer formation and progression. Elaboration of this topic can lead to a better understanding of oncogenic mechanisms, as well as the discovery of novel druggable proteins within the ubiquitin pathway.

Keywords: cancer; deubiquitination; deubiquitylation (deubiquitination); monoubiquitination; non-degradative pathways; polyubiquitin chain; signal transduction; therapeutic intervention; ubiquitination; ubiquitylation (ubiquitination).

FIGURE 1.

Functional consequence of different Ub chain topologies. The addition of a Ub moiety to a target protein is a multistep, ATP-dependent process catalyzed by three key enzymes: Ub-activating enzyme (E1), Ub-conjugating enzyme (E2), and Ub ligase (E3). Initially, the C-terminal carboxylate group of Ub is linked to E1 via a high energy thioester bond. E1 adenylates Ub and transfers it to one of its own cysteine residues, which is then shifted to a sulfhydryl group on one of the many E2 enzymes. Finally, E3 specifically catalyzes the transfer of ubiquitin from E2 to a lysine residue on the substrate protein; really interesting new gene (RING) E3 enzymes catalyze the direct transfer of Ub to the substrate, whereas homologous to the E6-AP C terminus (HECT) E3 enzymes transiently bind Ub via a thioester intermediate before the transfer of Ub. The end result is a mono- or polyubiquitinated protein, with different chain topologies engaging in different functional consequences.

FIGURE 2.

Ubiquitination is a key player in the activation of the NF-κB pathway. IκB is ubiquitinated with a Lys-48-linked chain, allowing for proteasomal degradation and transfer of NF-κB in to the nucleus. Lys-63-linked polyubiquitination, catalyzed by TRAF, acts as a docking site for TAB1-TAK1 activation. The IKK complex is also recruited, allowing for phosphorylation and activation by TAK1.