Format

Send to

Choose Destination
Oncogene. 2018 Oct;37(41):5552-5568. doi: 10.1038/s41388-018-0354-5. Epub 2018 Jun 13.

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

Author information

1
Department of Biomedical Science, Seoul, 110-799, Korea.
2
Ischemic/Hypoxic Disease Institute, Seoul, 110-799, Korea.
3
Department of Physiology, Seoul National University College of Medicine, Seoul, 110-799, Korea.
4
Laboratory for Medical Engineering, Graduate School of Engineering, Yokohama National University, Yokohama, 240-8501, Japan.
5
Department of Biomedical Science, Seoul, 110-799, Korea. chunys@snu.ac.kr.
6
Ischemic/Hypoxic Disease Institute, Seoul, 110-799, Korea. chunys@snu.ac.kr.
7
Department of Physiology, Seoul National University College of Medicine, Seoul, 110-799, Korea. chunys@snu.ac.kr.

Abstract

Neddylation is a cellular process that covalently conjugates substrate proteins with the small ubiquitin-like molecule NEDD8. As neddylation is required for fast turnover of proteins in proliferating cancer cells, the neddylation process is currently regarded as a potential target for cancer therapy. However, little is known about the role of neddylation in cancer invasion and metastasis. Unexpectedly, we here found that the neddylation blockade stimulates migration of lung cancer and glioblastoma cells. Mechanistically, C-CBL acts as the E3 ligase for neddylation of the proto-oncogene c-Src. After neddylation, c-Src is poly-ubiquitinated and degraded through the proteasome, which inhibits the PI3K-AKT pathway responsible for cell migration. In human lung cancer tissues, the downregulation of C-CBL was associated with c-Src/AKT, cancer metastasis, and poor survival in patients. Therefore, C-CBL is likely to play a tumor suppressive role by antagonizing a robust oncogenic signaling driven by c-Src. This study provides new insight about the role of neddylation in cancer metastasis. It also implies that the metastasis risk should be carefully evaluated before the clinical application of neddylation inhibitors as anticancer regimens.

PMID:
29899407
DOI:
10.1038/s41388-018-0354-5
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center