The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions

Abstract

BackgroundCullin-RING E3 ubiquitin ligase complexes play a central role in targeting cellular proteins for ubiquitination-dependent protein turnover through 26S proteasome. Cullin-2 is a member of the Cullin family, and it serves as a scaffold protein for Elongin B and C, Rbx1 and various substrate recognition receptors to form E3 ubiquitin ligases.Main body of the abstractFirst, the composition, structure and the regulation of Cullin-2 based E3 ubiquitin ligases were introduced. Then the targets, the biological functions of complexes that use VHL, Lrr-1, Fem1b, Prame, Zyg-11, BAF250, Rack1 as substrate targeting subunits were described, and their involvement in diseases was discussed. A small molecule inhibitor of Cullins as a potential anti-cancer drug was introduced. Furthermore, proteins with VHL box that might bind to Cullin-2 were described. Finally, how different viral proteins form E3 ubiquitin ligase complexes with Cullin-2 to counter host viral defense were explained.ConclusionsCullin-2 based E3 ubiquitin ligases, using many different substrate recognition receptors, recognize a number of substrates and regulate their protein stability. These complexes play critical roles in biological processes and diseases such as cancer, germline differentiation and viral defense. Through the better understanding of their biology, we can devise and develop new therapeutic strategies to treat cancers, inherited diseases and viral infections.

Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma

“…Therefore, Twist1 promoted Cul2 mRNA transcription but not translation. Cul2 has been predicted to be a tumor suppressor protein because of its association with the von Hippel-Lindau gene and ubiquitinated HIFa degradation (18,19). However, it has also been reported that Cul2 is required for normal vasculogenesis and involved in cell-cycle regulation (20) and that it promotes gastric cancer progression (35,36).…”

“…Cullin2 (Cul2) is a core component of multiple ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins. Cul2 was predicted to be a tumor-suppressor protein that degrades ubiquitinated HIFa (18,19). However, it has also been reported that Cul2 is required for normal vasculogenesis and is involved in cell-cycle regulation (20).…”

Functional roles of circular RNAs during epithelial-to-mesenchymal transition

“…Twist as an important EMT-TF that directly or indirectly governs the transcription of EMT-associated genes, thereby decreasing epithelial markers, such as E-cad, and increasing mesenchymal cell markers, including vimentin [54]. Cullin2 (Cul2) is a core component of multiple ElonginB/C-CUL2/5-SOCS-box protein (ECS) E3 ubiquitin-protein ligase complexes that mediate the ubiquitination of target proteins [55,56]. A study has validated that Twist1 promotes Cul2 transcription by binding to the Cul2 promoter and increases the pre-mRNA levels of Cul2.…”

The RNA-binding protein SERBP1 interacts selectively with the signaling protein RACK1

“…First isolated as a partner of specific protein kinase C isoforms, for which it was named receptor for activated C-kinase (4–8), RACK1 has also been shown to interact with a considerable number of other signal transduction proteins, including the cAMP-specific phosphodiesterase PDE4D5 (9–17), the tyrosine kinase oncoproteins SRC (18–21), FLT1 (22), and FAK (23), protein serine phosphatase PP2A (24–26), the MAPKs JNK1 and ERK1/2 (27), VARP (28), phospholipase C (29), the NMDA receptor (30–33), cytokine and growth factor receptors (34–38), G sβγ (39–42), selected 14.3.3 isoforms (43) and likely other signaling proteins (44–47). RACK1 also interacts with members of complexes that play important roles in protein degradation, such as the Cullin-2 based E3 ubiquitin ligases (48;48;49), as well as certain enzymes of unclear cellular function, such as inositol-requiring enzyme 1 (IRE1; refs, (50)). RACK1 also may interact with elements of the cytoskeleton, including β-integrins (51–56) and β-actin (21;21;57).…”