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

Guochang Huang1, Cameron Stock1, Claire C Bommeljé1

  • 1From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065.

The Journal of Biological Chemistry
|October 29, 2014
PubMed

Insights

SCCRO3, a protein involved in neddylation, acts as a tumor suppressor by inhibiting the neddylation activity of SCCRO, thus blocking cullin-RING ligase function and cell transformation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Biology

Background:

  • Cullin-RING type E3 ligases are crucial for ubiquitination and their activity is regulated by neddylation.
  • SCCRO/DCUN1D1 is a key regulator of neddylation, promoting nuclear translocation of the cullin-ROC1 complex for E3 ligase activity.
  • SCCRO3, a membrane-localized paralogue, has an unknown function in neddylation.

Purpose of the Study:

  • To investigate the role of SCCRO3 in neddylation and its potential E3 ligase activity.
  • To determine the mechanism by which SCCRO3 affects SCCRO-mediated neddylation and transformation.

Main Methods:

  • Binding assays to assess interactions between SCCRO3, CAND1, cullins, ROC1, and Ubc12.
  • Neddylation assays to evaluate SCCRO3's ability to promote or inhibit cullin neddylation.
  • Cellular localization studies to track the cullin-ROC1 complex in the presence of SCCRO3.
  • Transformation assays to assess SCCRO3's effect on SCCRO-induced cell transformation.

Main Results:

  • SCCRO3 binds to CAND1, cullins, and ROC1 but not Ubc12, and does not promote neddylation.
  • SCCRO3 sequesters cullins to the membrane, inhibiting nuclear translocation and SCCRO-promoted neddylation.
  • SCCRO3 inhibits SCCRO's transforming activity, requiring its myristoyl sequence and PONY domain for these functions.

Conclusions:

  • SCCRO3 lacks E3 ligase activity and functions as an antagonist to SCCRO-mediated neddylation.
  • Membrane localization and cullin binding are essential for SCCRO3's tumor suppressor function.
  • SCCRO3 acts as a tumor suppressor by inhibiting neddylation and cell transformation.
Keywords:
Head and Neck CancerLung CancerOncogeneTumor Suppressor GeneUbiquitin

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