Biology subjects

van de Kooij, B.

Publications and source records attributed to van de Kooij, B..

2 recordsLinked to original sources

bioRxiv2019

NEK10 tyrosine phosphorylates p53 and controls its transcriptional activity

In response to genotoxic stress, multiple kinase signalling cascades are activated, many of them directed towards the tumour suppressor p53 which coordinates the DNA damage response (DDR). Defects in DDR pathways lead to an accumulation of mutations that can promote tumorigenesis. Emerging evidence implicates multiple members of the NimA-related kinase (NEK) family (NEK1, NEK10 and NEK11) in the DDR. Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation through modulation of the p53-dependent transcriptional output, by directly phosphorylating p53 on Y327, revealing NEK10s unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response. Consistently, NEK10-deficient cells display heightened sensitivity to DNA damaging agents and low NEK10 expression is an independent predictor of a favorable response to radiation treatment in WT TP53 breast cancer patients.

cancer biology↗

bioRxiv2019

Comprehensive substrate specificity profiling of the human nek kinome reveals unexpected signaling outputs

Human NimA-related kinases (Neks) have multiple mitotic and non-mitotic functions, but few substrates are known. We systematically determined the phosphorylation-site motifs for the entire Nek kinase family, except for Nek11. While all Nek kinases strongly select for hydrophobic residues in the -3 position, the family separates into four distinct groups based on specificity for a serine versus threonine phospho-acceptor, and preference for basic or acidic residues in other positions. Unlike Nek1-Nek9, Nek10 is a dual-specificity kinase that efficiently phosphorylates itself and peptide substrates on serine and tyrosine, and its activity is enhanced by tyrosine auto-phosphorylation. Nek10 dual-specificity depends on residues in the HRD+2 and APE-4 positions that are uncommon in either serine/threonine or tyrosine kinases. Finally, we show that the phosphorylation-site motifs for the mitotic kinases Nek6, Nek7 and Nek9 are essentially identical to that of their upstream activator Plk1, suggesting that Nek6/7/9 function as phospho-motif amplifiers of Plk1 signaling.

biochemistry↗