Emerging role of Lys-63 ubiquitination in protein kinase and phosphatase activation and cancer development

Abstract

Ubiquitination is an important post-translational modification that has a pivotal role in numerous biological functions, such as cell growth, proliferation, apoptosis, DNA damage response, innate immune response and neuron degeneration. Although ubiquitination is thought to achieve these functions by targeting proteins for proteasome-dependent degradation, recent studies suggest that ubiquitination also has nonproteolytic functions, such as protein trafficking, kinase and phosphatase activation, which are involved in cell survival and cancer development. These progresses have advanced our current understanding of the novel functions of ubiquitination in signal transduction pathways and may provide novel paradigms for the treatment of human cancers.

Figure 1

Ubiquitination regulates protein degradation or activation. Ubiquitination reaction involves three enzymes. Ubiquitin is activated by the E1 and is transferred to the E2. The E3 provides substrate specificity by recognizing its protein substrates and bringing them to the E2, resulting in protein ubiquitination. Ubiquitin consists of seven lysine (K) residues, and ubiquitination chains involving those sites play important roles in regulating diverse fates of proteins. The K48-linked ubiquitination is recognized by the 26S proteasome and results in protein degradation. In contrast, the K63-linked ubiquitination does not induce protein degradation, instead it regulates signaling activation involved in distinct biological functions such as receptor endocytosis, DNA damage repair, protein trafficking, and signaling activation. Although other types of ubiquitin modifications are also observed, what exact role they play is less understood. Recent studies suggest that they can be involved in either protein degradation or non-proteolytic functions.

Figure 2

Ubiquitination regulates Akt stability and activation. Activation of IGF-1R by IGF-1 leads to TRAF6 activation. TRAF6 interacts with Akt and triggers K63-linked ubiquitination of Akt, in turn facilitating Akt membrane recruitment and subsequent phosphorylation by PDK1 and mTORC2. Active Akt then phosphorylates its substrates in the cytoplasm and nucleus to exert its biological functions. The termination of active Akt signaling can be achieved by E3 ligase TTC3 in the nucleus. TTC3 binds to active Akt in the nucleus and triggers Akt ubiquitination, perhaps through K48-linked modification, and degradation by the proteasome. TTC3 E3 ligase is activated by its phopshorylation at S378 by Akt, providing a negative feedback loop for Akt inactivation. In addition, Akt ubiquitination is promoted by CHIP or BRCA-1 and leads to Akt degradation.

Figure 3

The therapeutic strategies by targeting ubiquitination and deubiquitination pathways in the treatment of human cancers. (a) Small molecule inhibitors targeting TRAF6 may be considered as single or adjuvant agents for the treatment of human cancers. In addition, the therapeutic strategy by applying miR-145 and miR-146a for cancer treatment can be also considered. (b) Therapeutic strategies by targeting USP28 and USP2 can be considered, as they are shown to play an important role in stabilizing Myc and Cyclin D1. (c) A small molecular inhibitor targeting USP7 is shown to induce p53-dependent apoptosis by stabilizing p53, suggesting that the targeting of USP7 is a potential strategy for human cancers.