Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

Abstract

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

Keywords: AIRE, autoimmune regulator; AKT, AKT serine/threonine kinase; ATR, ataxia telangiectasia-mutated and Rad3-related; BCL2, BCL2 apoptosis regulator; BMAL1, aryl hydrocarbon receptor nuclear translocator like; CDK2/4, cyclin dependent kinase 2/4; CDT2, denticleless E3 ubiquitin protein ligase homolog; CHK1, checkpoint kinase 1; CK1/2, casein kinase I/II; CLOCK, clock circadian regulator; COMMD1, copper metabolism domain containing 1; CRL, cullin-RING ligase; CRY1, cryptochrome circadian regulator 1; CSN, COP9 signalosome; Ci, cubitus interruptus; Crosstalk; Cullin-RING ligases; DDB1, damage specific DNA binding protein 1; DYRK1A/B, dual-specificity tyrosine-phosphorylation-regulated kinases 1A/B; Degradation; EMT, epithelial–mesenchymal transition; ERG, ETS transcription factor ERG; ERK, mitogen-activated protein kinase 1; EXO1, exonuclease 1; FBW7, F-box and WD repeat domain containing 7; FBXL3, F-box and leucine rich repeat protein; FBXO3/31, F-box protein 3/31; FZR1, fizzy and cell division cycle 20 related 1; HCC, hepatocellular carcinomas; HIB, Hedghog-induced MATH and BTB domain-containing protein; HIF1α, NF-κB and hypoxia inducible factor 1 subunit alpha; ID2, inhibitor of DNA binding 2; JAB1, c-Jun activation domain binding protein-1; KBTBD8, kelch repeat and BTB domain containing 8; KDM2B, lysine demethylase 2B; KEAP1, kelch like ECH associated protein 1; KLHL3, kelch like family member 3; KRAS, KRAS proto-oncogene, GTPase; Kinases; MYC, MYC proto-oncogene, bHLH transcription factor; NEDD8, NEDD8 ubiquitin like modifier; NOLC1, nucleolar and coiled-body phosphoprotein 1; NRF2, nuclear factor, erythroid 2 like 2; P-TEFb, positive transcription elongation factor b; PDL1, programmed death ligand 1; PKC, protein kinase C; PKM2, pyruvate kinase M2 isoform; PYGO2, pygopus 2; Phosphorylation; RA, retinoic acid; RARα, RA receptor α; RRM2, ribonucleotide reductase regulatory subunit M2; SNAIL1, snail family transcriptional repressor 1; SOCS6, suppressor of cytokine signaling 6; SPOP, speckle-type POZ protein; SRC-3, nuclear receptor coactivator 3; TCN, triciribine hydrate; TCOF1, treacle ribosome biogenesis factor 1; TRF1, telomeric repeat binding factor 1; Targeted therapy; Tumorigenesis; USP37, ubiquitin specific peptidase 37; Ubiquitination; VHL, von Hippel-Lindau tumor suppressor; Vps34, phosphatidylinositol 3-kinase catalytic subunit type 3; XBP1, X-box binding protein 1; ZBTB16, zinc finger and BTB domain containing 16; c-Fos, Fos proto-oncogene, AP-1 transcription factor subunit; p130Cas, BCAR1 scaffold protein, Cas family member.