Acute Myeloid Leukemia-Related Proteins Modified by Ubiquitin and Ubiquitin-like Proteins

Abstract

Acute myeloid leukemia (AML), the most common form of an acute leukemia, is a malignant disorder of stem cell precursors of the myeloid lineage. Ubiquitination is one of the post-translational modifications (PTMs), and the ubiquitin-like proteins (Ubls; SUMO, NEDD8, and ISG15) play a critical role in various cellular processes, including autophagy, cell-cycle control, DNA repair, signal transduction, and transcription. Also, the importance of Ubls in AML is increasing, with the growing research defining the effect of Ubls in AML. Numerous studies have actively reported that AML-related mutated proteins are linked to Ub and Ubls. The current review discusses the roles of proteins associated with protein ubiquitination, modifications by Ubls in AML, and substrates that can be applied for therapeutic targets in AML.

Keywords: ISGylation; NEDDylation; SUMOylation; deubiquitination; ubiquitination.

Figure 1

An enzymatic cascade of Ub and Ubls, and deconjugating enzymes. Ub and Ubls are conjugated to target substrates by an enzymatic cascade involving E1, E2, and E3. A modifier is first activated by an E1 activating enzyme and is transferred onto an E2 conjugating enzyme. Subsequently, E3 ligase interacts simultaneously with a modifier-loaded E2 and the target protein, and induces an isopeptide bond between the C-terminus of modifier and a lysine residue of the substrate. Once a modifier is conjugated to their targets, polypeptide chains are formed due to the presence of suitable motifs on modifiers. Deconjugating enzymes are responsible for the reverse process of the modification.

Figure 2

Schematic diagram of the FLT3-ITD signaling pathway. c-Cbl ubiquitinates and induces proteasomal degradation of FLT3-ITD, whereas c-Cbl mutant (R420Q) could not ubiquitinate. USP9X and USP10 deubiquitinate and increase the stability of FLT3-ITD.

Figure 3

Schematic diagram of the C/EBPα signaling pathway. TRIB1 binds to COP1 and enhances its ubiquitin ligase activity. COP1 and SCF^Skp2 ubiquitinate and induce proteasomal degradation of FLT3-ITD. TRIB2 binds and promotes proteasome-dependent C/EBPα degradation.