HEY1 functions are regulated by its phosphorylation at Serine 68

Abstract

Resumen del póster presentado al 2nd Symposium on Biomedical Research: "Advances and perspectives in cancer", celebrado en Madrid el 17 de abril de 2015.HEY1 is a member of the bHLH-O family of transcription repressors. HEY1 is a downstream effector of Notch signalling pathway, although other cancer-related pathways also regulate its expression. HEY1 acts as a positive regulator of the tumour suppressor p53 via still unknown mechanisms. A MALDI-TOF/TOF mass spectrometry analysis has uncovered a novel HEY1 regulatory phosphorylation event at the serine 68. Strikingly, this single phosphorylation event controls HEY1 stability and function: simulation of HEY1 serine 68 phosphorylation increases HEY1 protein stability but inhibits its ability to enhance p53 transcriptional activity. Unlike wild-type HEY1, expression of the phosphomimetic mutant HEY1-S68D failed to induce p53-dependent cell cycle arrest and it did not sensitize U2OS cells to p53-activating chemotherapeutic drugs. We have identified Serine/threonine kinase 38 (STK38) as one of the protein kinases responsible for HEY1 serine 68 phosphorylation. A subpopulation of STK38 localizes to centrosomes in a cell-cycle-dependent manner and contributes to the regulation of centrosome duplication. In accordance with this we observe that HEY1 is phosphorylated at serine 68 during mitosis and it also accumulates in the centrosomes of mitotic cells. Our results indicate that HEY1 phosphorylation at residue Ser-68 could play a crucial role in the regulation of HEY1 functions in vivo and suggest a novel function for HEY1 in the regulation of centrosome cycle.Peer reviewe