SCCRO3 (DCUN1D3) antagonizes the neddylation and oncogenic activity of SCCRO (DCUN1D1)

J Biol Chem. 2014 Dec 12;289(50):34728-42. doi: 10.1074/jbc.M114.585505. Epub 2014 Oct 27.

Abstract

The activity of cullin-RING type ubiquitination E3 ligases is regulated by neddylation, a process analogous to ubiquitination that culminates in covalent attachment of the ubiquitin-like protein Nedd8 to cullins. As a component of the E3 for neddylation, SCCRO/DCUN1D1 plays a key regulatory role in neddylation and, consequently, cullin-RING ligase activity. The essential contribution of SCCRO to neddylation is to promote nuclear translocation of the cullin-ROC1 complex. The presence of a myristoyl sequence in SCCRO3, one of four SCCRO paralogues present in humans that localizes to the membrane, raises questions about its function in neddylation. We found that although SCCRO3 binds to CAND1, cullins, and ROC1, it does not efficiently bind to Ubc12, promote cullin neddylation, or conform to the reaction processivity paradigms, suggesting that SCCRO3 does not have E3 activity. Expression of SCCRO3 inhibits SCCRO-promoted neddylation by sequestering cullins to the membrane, thereby blocking its nuclear translocation. Moreover, SCCRO3 inhibits SCCRO transforming activity. The inhibitory effects of SCCRO3 on SCCRO-promoted neddylation and transformation require both an intact myristoyl sequence and PONY domain, confirming that membrane localization and binding to cullins are required for in vivo functions. Taken together, our findings suggest that SCCRO3 functions as a tumor suppressor by antagonizing the neddylation activity of SCCRO.

Keywords: Head and Neck Cancer; Lung Cancer; Oncogene; Tumor Suppressor Gene; Ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Carcinogenesis*
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cullin Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • NEDD8 Protein
  • Protein Structure, Tertiary
  • Proteins
  • Proto-Oncogene Proteins / metabolism*
  • RNA-Binding Proteins / metabolism
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitins / metabolism*

Substances

  • CAND1 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cullin Proteins
  • DCUN1D1 protein, human
  • DCUN1D3 protein, human
  • Intracellular Signaling Peptides and Proteins
  • NEDD8 Protein
  • NEDD8 protein, human
  • PUM2 protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • RBX1 protein, human
  • RNA-Binding Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitins