Novel Serine 176 phosphorylation of YBX1 activates NF-{kappa}B in colon cancer [Cell Biology]

The Y box protein 1 (YBX1) is a well-known oncoprotein which has tumor promoting functions. YBX1 is widely considered to be an attractive therapeutic target in cancer. In order to develop novel therapeutics to target YBX1, it is of great importance to understand how YBX1 is finely regulated in cancer. Previously, we have shown that YBX1 could function as a tumor promoter through phosphorylation of its serine 165 (S165) residue, leading to the activation of the NF-[kappa]B signaling pathway (1). In this study, using mass spectrometry analysis, we discovered a quite distinct phosphorylation site, S176, on YBX1. Overexpression of the YBX1-S176A (serine to alanine) mutant in either HEK293 cells or colon cancer HT29 cells showed a dramatically reduced NF-[kappa]B activating ability as compared with that of WT-YBX1, confirming that S176 phosphorylation is critical for the activation of NF-[kappa]B by YBX1. Importantly, the mutant of S176 and the previously reported S165 sites regulate distinct groups of NF-[kappa]B target genes, suggesting the unique and irreplaceable function of each of these two phosphorylated serine residues. Our important findings could provide a novel cancer therapeutic strategy by blocking either S176 or S165 phosphorylation or both of YBX1 in colon cancer.

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