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.

Multiple functions of DYRK2 in cancer and tissue development

“…B) . In contrast to genotoxic conditions, DYRK2 activity for phosphorylation of p53 is negatively regulated by hypoxia condition via SIAH2‐dependent DYRK2 polyubiquitination and degradation . More recently, Xu et al .…”

Ubiquitin ligases in oncogenic transformation and cancer therapy

“…Members of the SIAH RING-finger family (SIAH1 and SIAH2) play important roles in fine-tuning the cellular response to 96–98 and the (UPR) 99 . Under hypoxic conditions, transcription and protein phosphorylation of SIAH1 and SIAH2 are upregulated, increasing their abundance and activity 96,97,100 . Activated SIAH1 and SIAH2 degrade prolyl hydroxylase 1 and prolyl hydroxylase 3, which limits prolyl hydroxylation of the transcription factor hypoxia-inducible factor 1α (HIF1α) and prevents its degradation by VHL 97 .…”

Regulators and Effectors of Siah Ubiquitin Ligases

“…p38 MAPK phosphorylates serine 29, and threonines 24 and 29 of Siah2, which increases its activity towards selected substrates, including prolyl hydroxylase 3 (PHD3) (51). Similarly, hypoxia induces phosphorylation of serines 16, 28, and 69 and threonines 26 and 119 of Siah2 by DYRK2 (dual specificity tyrosine-phosphorylation-regulated kinase 2), which results in increased Siah2-dependent ubiquitination and degradation of PHD3 (52). Under normoxic conditions, homeodomain-interacting protein kinase 2 (HIPK2) phosphorylates Siah2 at positions 26, 28, and 68, destabilizing Siah2 and weakening its interactions with substrates.…”