Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein
"> Graphical abstract
"> Figure 1
<p>Unified model for Mcl-1 regulation of Bak-dependent mitochondrial outer membrane permeabilization (MOMP). Mcl-1 and Bak are constitutively anchored to the outer mitochondrial membrane (OMM). Mcl-1 can directly bind Bak and maintain it in an inactive conformation. Alternatively, Mcl-1 can sequester direct activator BH3-only proteins, such as Bim, and prevent them from activating Bak. Sensitizer BH3-only proteins, such as Noxa, can relieve Bak inhibition by competing with Mcl-1 for binding the BH3 domain of Bak. Activated Bak forms pore in the OMM to release cytochrome c, activate caspases and induce apoptosis. Similar mechanisms are relevant for Bax/Mcl-1 interactions.</p> "> Figure 2
<p>Schematic representation of the human Mcl-1 protein showing the functional regions and post-translational modification sites. These include the transmembrane domain (TM), Bcl-2 homology domains (BH1-4), weak (lower case) and strong (upper case) PEST sequences, sites of ubiquitination (Ub), caspase cleavage and phosphorylation sites.</p> "> Figure 3
<p>Regulation of Mcl-1 stability. Mcl-1 can be phosphorylated by several protein kinases (in blue) at indicated residues. In interphase or post-mitotic cells, JNK phosphorylates Thr163 which primes Mcl-1 for phosphorylation by GSK3 at Ser159 and Ser155. During prolonged mitotic arrest, p38, CKII and JNK phosphorylate Ser121, Ser159 and Thr163. CDK1 may indirectly enhance phosphorylation at these sites by phosphorylating Thr92, thereby triggering the dissociation of the phosphatase PP2A that would otherwise dephosphorylate Mcl-1. Phosphorylation of Ser155, Ser159 and Thr163 drives the recognition of Mcl-1 by its E3 ubiquitin-ligases SCF<sup>β-TrCP</sup>, SCF<sup>Fbw7</sup> and Trim17 (in black). In addition, phosphorylation at Thr92 is required for Cdc20-mediated ubiquitination of Mcl-1, although direct ubiquitination of Mcl-1 by APC/C<sup>Cdc20</sup> has not been demonstrated. In addition, the E3 ubiquitin-ligase Mule can interact either with the C-terminus of Mcl-1 through its BH3 domain, or within the N-terminal 30 amino acids of Mcl-1. Binding of Mule does not depend on Mcl-1 phosphorylation but it can be inhibited by the BH3-only proteins Bim and Puma. In contrast, Noxa increases the association between Mule and Mcl-1 through an as yet unknown mechanism. Ubiquitination of Mcl-1 targets it for proteasomal degradation. It can be opposed by the deubiquitinase USP9X that directly removes degradative Lys-48-linked polyubiquitin chains from Mcl-1, which results in Mcl‑1 stabilization. Phosphorylation at Ser155, Ser159 and Thr163 inhibits the binding of USP9X to Mcl-1. In cancer cells in which Mcl-1 degradation is not dependent on GSK3, ERK-mediated phosphorylation of Thr163 stabilizes Mcl-1 (not depicted here).</p> ">
Abstract
:1. Introduction
1.1. The Bcl-2 Family
1.2. The Ubiquitin-Proteasome Machinery
2. Mcl-1 is a Crucial Prosurvival Protein
3. Multi-Level Regulation of Mcl-1
3.1. Transcriptional, Post-Transcriptional and Translational Regulation of Mcl-1
3.2. Post-Translational Regulation of Mcl-1
4. Control of Mcl-1 Protein Level by the Ubiquitin-Proteasome System
4.1. The E3 Ubiquitin-Ligases of Mcl-1
4.1.1. Mule
4.1.2. Phosphorylation-Dependent Degradation of Mcl-1
4.1.3. SCFβ-TrCP
4.1.4. SCFFbw7
4.1.5. APC/CCdc20
4.1.6. Trim17
4.2. Deubiquitination of Mcl-1 by USP9X
4.3. Ubiquitin-Independent Degradation of Mcl-1
5. Conclusions
Acknowledgments
Conflicts of Interest
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Mojsa, B.; Lassot, I.; Desagher, S. Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein. Cells 2014, 3, 418-437. https://doi.org/10.3390/cells3020418
Mojsa B, Lassot I, Desagher S. Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein. Cells. 2014; 3(2):418-437. https://doi.org/10.3390/cells3020418
Chicago/Turabian StyleMojsa, Barbara, Iréna Lassot, and Solange Desagher. 2014. "Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein" Cells 3, no. 2: 418-437. https://doi.org/10.3390/cells3020418