title: Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways.
abstract: The ubiquitin E3 ligase SIAH2 is an important regulator of the hypoxic response as it leads to the ubiquitin/proteasomal degradation of prolyl hydroxylases such as PHD3, which in turn increases the stability of hypoxia-inducible factor (HIF)-1α. In the present study, we identify the serine/threonine kinase DYRK2 as SIAH2 interaction partner that phosphorylates SIAH2 at five residues (Ser16, Thr26, Ser28, Ser68, and Thr119). Phosphomimetic and phospho-mutant forms of SIAH2 exhibit different subcellular localizations and consequently change in PHD3 degrading activity. Accordingly, phosphorylated SIAH2 is more active than the wild-type E3 ligase and shows an increased ability to trigger the HIF-1α-mediated transcriptional response and angiogenesis. We also found that SIAH2 knockdown increases DYRK2 stability, whereas SIAH2 expression facilitates DYRK2 polyubiquitination and degradation. Hypoxic conditions cause a SIAH2-dependent DYRK2 polyubiquitination and degradation which ultimately also results in an impaired SIAH2 phosphorylation. Similarly, DYRK2-mediated phosphorylation of p53 at Ser46 is impaired under hypoxic conditions, suggesting a molecular mechanism underlying chemotherapy resistance in solid tumors.
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain.
authors.forename: Moisés
authors.initials: M
authors.lastname: Pérez
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Limones
authors.forename: Inés
authors.initials: I
authors.lastname: Zapico
authors.forename: Anabel
authors.initials: A
authors.lastname: Marina
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
mesh_terms: D000818:Animals; D001665:Binding Sites; D015687:Cell Hypoxia; D002460:Cell Line; D004249:DNA Damage; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000097603:Dyrk Kinases; D000098563:Seven in Absentia Proteins
chemical_list: D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000097603:Dyrk Kinases; D000098563:Seven in Absentia Proteins