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Cullin RING Ligase 5 (CRL-5): Neddylation Activation and Biological Functions

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Cullin-RING Ligases and Protein Neddylation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1217))

Abstract

Cullin-5 (Cul-5) was originally identified as an arginine vasopressin (AVP) receptor due to its homology to a vasopressin-activated calcium-mobilizing protein 1 (VACM-1). Cul-5 has subsequently gained much attention after being identified as the key component of CRL-5 (Cullin-RING ligase-5) that mediates ubiquitylation and degradation of several key cellular proteins associated with human cancers and viral infections. Structurally, Cul-5 interacts with the Elongin B/C complex, a RING finger protein (RBX2/SAG), and a SOCS protein to form a CRL-5 E3 ubiquitin ligase protein complex. CRL-5, by controlling turnover of a variety of substrates, is implicated in several biological processes and human diseases. Activation of CRL-5 requires Cul-5 neddylation, catalyzed by a neddylation enzyme cascade, consisting of the E1 NEDD8-activating enzyme (NAE), the E2 neddylation conjugating enzyme (UBE2F), and E3 neddylation ligase (RBX2/SAG). RBX2/SAG, therefore, serves as both Cul-5 neddylation E3 and CRL-5 ubiquitylation E3. Here, we review the current knowledge on CRL-5, its activation by the UBE2F-SAG, its regulation of various signaling pathways via substrate degradation, and its implications in human cancers.

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Abbreviations

APOBEC3G:

Apolipoprotein B editing complex 3G

APS:

Adapter protein with a pleckstrin homology and Src homology 2 domain

AVP:

Arginine vasopressin

CAND1:

Cullin-associated neddylation-dissociated 1

CH:

Cullin homology

CKB:

Cytosolic creatine kinase

CR:

Cullin repeats

CRL-5:

Cullin RING ligase 5

CRLs:

Cullin-RING ligases

CSN:

COP9 signalosome complex

CTD:

Carboxyl-terminal domain

Cul-5:

Cullin-5

DCNL:

The defective in cullin neddylation protein-like proteins

DSBs:

Double-stranded DNA breaks

EBV:

Epstein-Barr virus

ER:

Endoplasmic reticulum

FAK:

Focal adhesion kinase

HAdV:

Human adenoviruses

HIF-α:

Hypoxia-inducible factor-α

HIPK2:

Homeodomain-interacting protein kinase 2

HIV-1:

Human immunodeficiency virus-1

HSP90:

Heat shock protein 90

ID2:

Inhibitor of DNA binding 2

iNOS:

Inducible nitric oxide synthase

IRS4:

Insulin receptor substrate 4

JAK2:

Janus kinase 2

KSHV:

Kaposi’s sarcoma-associated herpesvirus

LANA:

Latency-associated nuclear antigen

LPS:

Lipopolysaccharide

LRRK2:

Leucine-rich repeat kinase 2

MCK:

Mitochondrial creatine kinase

MLL:

Mixed-lineage leukemia

MuHV-4:

Murid herpesvirus-4

NAE:

NEDD8-activating enzyme

NHEJ:

Nonhomologous end-joining DNA repair system

NSCLC:

Non-small lung cancers

NTD:

Amino-terminal domain

PTHrP:

Parathyroid hormone-related peptide

RBX2:

RING-box protein 2

ROS:

Reactive oxygen species

Rpb1:

RNA polymerase II B1

SAG:

Sensitive to apoptosis gene

SCLC:

Small cell lung cancers

SH2:

Src homology 2

SOCS:

Suppressor of cytokine signaling

TCGA:

The Cancer Genome Atlas

TNF-R2:

Tumor necrosis factor receptor 2

TRIAD1:

Two RING finger and double RING finger linked 1

VACM-1:

Vasopressin-activated calcium-mobilizing protein 1

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Authors and Affiliations

  1. Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Shizhen Zhang & Yi Sun

  2. Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Yi Sun

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  1. Shizhen Zhang
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  1. Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Yi Sun

  2. Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Wenyi Wei

  3. Life Science Institute, Zhejiang University, Hangzhou, China

    Jianping Jin

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Zhang, S., Sun, Y. (2020). Cullin RING Ligase 5 (CRL-5): Neddylation Activation and Biological Functions. In: Sun, Y., Wei, W., Jin, J. (eds) Cullin-RING Ligases and Protein Neddylation. Advances in Experimental Medicine and Biology, vol 1217. Springer, Singapore. https://doi.org/10.1007/978-981-15-1025-0_16

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