title: C-terminal Src kinase (Csk)-mediated phosphorylation of eukaryotic elongation factor 2 (eEF2) promotes proteolytic cleavage and nuclear translocation of eEF2.
abstract: 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.affiliation: From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yao
authors.forename: Bing-Qian
authors.initials: BQ
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Deirdre
authors.initials: D
authors.lastname: McGarrigle
authors.forename: Bo-Wen
authors.initials: BW
authors.lastname: Xing
authors.forename: Mao-Tian
authors.initials: MT
authors.lastname: Zhou
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: J Jillian
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Huang
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
mesh_terms: D021581:Active Transport, Cell Nucleus; D000782:Aneuploidy; D000818:Animals; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020652:Peptide Elongation Factor 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D059748:Proteolysis; D034622:RNA Interference; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D058207:Sumoylation; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020652:Peptide Elongation Factor 2; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: Cancer Biology; Csk; Nuclear Pleomorphism; Nuclear Translocation; Phosphorylation; Proteolytic Cleavage; Sumoylation; Translation Elongation Factors