K63-linked ubiquitination in kinase activation and cancer - PubMed (original) (raw)

K63-linked ubiquitination in kinase activation and cancer

Guocan Wang et al. Front Oncol. 2012.

Abstract

Ubiquitination has been demonstrated to play a pivotal role in multiple biological functions, which include cell growth, proliferation, apoptosis, DNA damage response, innate immune response, and neuronal degeneration. Although the role of ubiquitination in targeting proteins for proteasome-dependent degradation have been extensively studied and well-characterized, the critical non-proteolytic functions of ubiquitination, such as protein trafficking and kinase activation, involved in cell survival and cancer development, just start to emerge, In this review, we will summarize recent progresses in elucidating the non-proteolytic function of ubiquitination signaling in protein kinase activation and its implications in human cancers. The advancement in the understanding of the novel functions of ubiquitination in signal transduction pathways downstream of growth factor receptors may provide novel paradigms for the treatment of human cancers.

Keywords: Akt; NF-κB; TRAF6; phosphorylation; protein kinase; tumorigenesis; ubiquitination.

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Figures

Figure 1

Figure 1

(A) Ubiquitin, a 76-amino acid protein, is highly evolutionarily conserved across species. It contains seven lysine (K) residues (K6, K11, K27, K29, K33, K48, and K63) in the ubiquitin, which have been identified to be utilized for ubiquitination chains. (B) In the ubiquitination process, ubiquitin is covalently conjugated to lysine residues of substrate proteins through a three-step enzymatic reaction. Ubiquitin is first activated by ubiquitin-activating enzyme (E1). The activated ubiquitin is then delivered to the ubiquitin-conjugating enzyme (E2), which will be transferred from the E2 to a lysine residue of a target protein by ubiquitin ligase (E3). The function usefulness of ubiquitin conjugation is not limited to the ubiquitin–proteasome pathway. Mono- and polyubiquitins are used as signals in various pathways including endocytosis, DNA repair, apoptosis, and transcriptional regulation.

Figure 2

Figure 2

The role of K63-linked polyubiquitination in the activation of canonical and non-canonical NF-κB signaling pathway. In both canonical and non-canonical NF-κB pathways, ligand binding to receptors results in the recruitment of the TNF receptor-associated factors (TRAFs) to the receptors. In the canonical pathway, the recruitment of E3 ligase TRAF6promotesits auto-polyubiquitinating and other neighboring target proteins via K63-linked polyubiquitin chains. Unanchored free K63-linked polyubiquitin then directly activate TAK1 kinase, which then phosphorylates and activates IKK-β to induce NF- κB activation. In the non-canonical pathway, TRAF3, TRAF2, and cIAP promote rapid proteasomal degradation of NIK by the ubiquitin–proteasome system under un-stimulated condition. Various stimuli release NIK from TRAF3 inhibition by triggering cIAP activation by TRAF2-mediated K63-polyubiquitination and subsequent degradation of TRAF3. NIK-mediated-phosphorylation of p100 and its subsequent processing promotes RelB/p52 nuclear translocation and NF- κB activation.

Figure 3

Figure 3

Ubiquitination regulates Akt stability and activation. IGF-1-induced activation of IGF-1R promotes TRAF6 activation, which then triggers K63-linked ubiquitination of Akt and promotes 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. E3 ligase TTC3 has been suggested to play a role in the termination of active Akt signaling in the nucleus by promoting Akt ubiquitination and degradation by the proteasome. TTC3 activity is regulated by Akt-mediated phosphorylation at S378, thus providing a negative feedback loop for Akt inactivation. In addition, Akt ubiquitination is promoted by CHIP or BRCA1 and leads to Akt degradation.

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