Differential functions of TLE1 and TLE3 depending on a specific phosphorylation site.
Mammalian Transducin-like enhancer of split (TLE) confer global repression of numerous target genes in conjunction with a myriad of DNA-binding repressors. These factors have a major role in the regulation of multiple signal transduction pathways. Evidence have been obtained regarding the possible role of some of these proteins in cancer. TLE3 was suggested as a marker for increased chemosensitivity from pathological studies. Here we demonstrate, using the TCGA data base, differences in expression of this gene compared to TLE1 in several cancers. In-vitro transduction of a retrovirus encoding TLE3 to A549 lung cancer cells increased paclitaxel effectivity while TLE1 introduction to these cells decreased it. While TLE1 and TLE3 share ∼80% amino acid identity, we show that mutating or reconstituting an amino-terminal phosphorylation site, which is present only in TLE1 but absent from TLE3, and is evolutionary conserved, converts the activity of TLE1 to that of TLE3 like and vice versa. We repeated these results in an adipocytes differentiation system. Our results reveal how a single phosphorylation site can confer distinct qualitative or quantitative activities on highly homologous transcriptional regulators.
['Kornspan|David|D|', 'Smith|Yoav|Y|', 'Nechushtan|Hovav|H|']
D000072283:A549 Cells D017667:Adipocytes D000595:Amino Acid Sequence D019943:Amino Acid Substitution D000818:Animals D001665:Binding Sites D014408:Biomarkers, Tumor D002454:Cell Differentiation D002460:Cell Line D056970:Co-Repressor Proteins D017124:Conserved Sequence D005786:Gene Expression Regulation D006801:Humans D008175:Lung Neoplasms D020935:MAP Kinase Signaling System D051379:Mice D016297:Mutagenesis, Site-Directed D010766:Phosphorylation D011994:Recombinant Proteins D017386:Sequence Homology, Amino Acid D043823:Taxoids
TLE1 TLE3 Chemosensitivity Site specific phosphorylation