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

Authors: Huang, G.; Stock, C.; Bommeljé, C. C.; Weeda, V. B.; Shah, K.; Bains, S.; Buss, E.; Shaha, M.; Rechler, W.; Ramanathan, S. Y.; Singh, B.
Article Title: SCCRO3 (DCUN1D3) antagonizes the neddylation and oncogenic activity of SCCRO (DCUN1D1)
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: biochemistry; inhibitory effect; tumor suppressors; nuclear translocations; ubiquitin-like proteins; transforming activity; oncogenic activities; covalent attachment; membrane localization
Journal Title: Journal of Biological Chemistry
Volume: 289
Issue: 50
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2014-12-12
Start Page: 34728
End Page: 34742
Language: English
DOI: 10.1074/jbc.M114.585505
PROVIDER: scopus
PMCID: PMC4263876
PUBMED: 25349211
Notes: Export Date: 2 January 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Bhuvanesh Singh
    219 Singh
  2. Guochang Huang
    15 Huang
  3. Viola Benedicte Weeda
    3 Weeda
  4. Sarina Bains
    19 Bains
  5. Cameron   Stock
    4 Stock
  6. Manish A Shaha
    4 Shaha