Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 18, Pages 12666-12678Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.546481
Keywords
Cancer Biology; Nuclear Translocation; Phosphorylation; Sumoylation; Translation Elongation Factors; Csk; Nuclear Pleomorphism; Proteolytic Cleavage
Categories
Funding
- National Institutes of Health [HL091525]
- National Science Foundation of China [31028015, 31221061]
- National Basic Research Program of China [2013CB911102]
- 111 Project of China [B06018]
Ask authors/readers for more resources
Background: The C-terminal Src kinase (Csk) is known as a tumor suppressor, but Src-independent function is unclear. Results: eEF2 is a new protein substrate of Csk. Conclusion: eEF2 phosphorylation and SUMOylation promote its proteolytic cleavage and nuclear localization. Significance: Our findings suggest that a tyrosine kinase can be both a tumor suppressor and a promoter through regulation of different substrate proteins. Protein-tyrosine kinase C-terminal Src kinase (Csk) was originally purified as a kinase for phosphorylating Src and other Src family kinases. The phosphorylation of a C-terminal tyrosine residue of Src family kinases suppresses their kinase activity. Therefore, most physiological studies regarding Csk function have been focused on Csk as a negative regulator of Src family tyrosine kinases and as a potential tumor suppressor. Paradoxically, the protein levels of Csk were elevated in some human carcinomas. In this report, we show that eukaryotic elongation factor 2 (eEF2) is a new protein substrate of Csk and could locate in the nucleus. We demonstrate that Csk-mediated phosphorylation of eEF2 has no effect on its cytoplasmic function in regulating protein translation. However, phosphorylation of eEF2 enhances its proteolytic cleavage and the nuclear translocation of the cleaved eEF2 through a SUMOylation-regulated process. Furthermore, we show that cleaved fragments of eEF2 can induce nuclear morphological changes and aneuploidy similar to those in cancer cells, suggesting that there is an additional mechanism for Csk in tumorigenesis through regulation of eEF2 subcellular localization.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available