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In Vitro Analysis of E3 Ubiquitin Ligase Function
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In Vitro Analysis of E3 Ubiquitin Ligase Function

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The E3 ligase C-CBL inhibits cancer cell migration by neddylating the proto-oncogene c-Src

Gun-Woo Lee1, Jun Bum Park1, Sung Yeon Park1,2

  • 1Department of Biomedical Science, Seoul, 110-799, Korea.

Oncogene
|June 15, 2018
PubMed

Insights

Blocking neddylation unexpectedly enhances cancer cell migration by stabilizing c-Src. This study reveals C-CBL

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Neddylation, a process involving NEDD8 conjugation, is crucial for protein turnover in cancer cells.
  • Neddylation is a potential cancer therapy target, but its role in metastasis is unclear.

Purpose of the Study:

  • To investigate the role of neddylation in cancer invasion and metastasis.
  • To elucidate the molecular mechanisms by which neddylation affects cancer cell migration.

Main Methods:

  • Investigated the effect of neddylation blockade on lung cancer and glioblastoma cell migration.
  • Identified C-CBL as the E3 ligase for neddylation of c-Src.
  • Analyzed the ubiquitination, degradation, and signaling pathways involved.

Main Results:

  • Neddylation blockade unexpectedly stimulated lung cancer and glioblastoma cell migration.
  • C-CBL-mediated neddylation of c-Src leads to its proteasomal degradation.
  • Degradation of c-Src inhibits the PI3K-AKT pathway, a key driver of cell migration.
  • Downregulation of C-CBL in lung cancer tissues correlated with increased metastasis and poor patient survival.

Conclusions:

  • C-CBL acts as a tumor suppressor by antagonizing c-Src-driven oncogenic signaling.
  • Neddylation blockade may promote cancer metastasis, necessitating careful evaluation before clinical use.
  • This study offers novel insights into neddylation's role in cancer metastasis.

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