Phosphorylation of eEF1A1 at Ser300 by TβR-I results in inhibition of mRNA translation.
BACKGROUND
Transforming growth factor β (TGF-β) is a potent inhibitor of cell proliferation that regulates cell functions by activating specific serine/threonine kinase receptors on the cell surface. Type I TGF-β receptor (TβR-I) is essential for TGF-β signaling, and substrates of TβR-I provide insights into molecular mechanisms of TGF-β signaling.


RESULTS
Here we identify eukaryotic elongation factor 1A1 (eEF1A1) as a novel substrate of TβR-I. We show that TβR-I phosphorylates eEF1A1 at Ser300 in vitro and in vivo. Ser300 was found to be important for aminoacyl-tRNA (aa-tRNA) binding to eEF1A1. Ser300 phosphorylation or mutations of Ser300 correlate with inhibition of protein synthesis in vitro and in vivo. We show that mimicking eEF1A1 phosphorylation at Ser300 results in inhibition of cell proliferation, and that mutations of Ser300 affect TGF-β dependency in inhibition of protein synthesis and cell proliferation. Increased expression of eEF1A has been reported to enhance carcinogenesis. An analysis of human breast cancer cases revealed a decrease of eEF1A1 phosphorylation at Ser300 in malignant tumor cells as compared to epithelial cells in noncancerous tissues.


CONCLUSIONS
Phosphorylation of eEF1A1 by TβR-I is a novel regulatory mechanism that provides a direct link to regulation of protein synthesis by TGF-β, as an important component in the TGF-β-dependent regulation of protein synthesis and cell proliferation.
Lin
Kah Wai
KW
Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Yakymovych
Ihor
I
Jia
Min
M
Yakymovych
Mariya
M
Souchelnytskyi
Serhiy
S
D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*
C094814:EEF1A1 protein, human; D020648:Peptide Elongation Factor 1; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I