E3 ubiquitin-protein ligase SIAH2 (SIAH2) (SIAH2)

E3 ubiquitin-protein ligase SIAH2 (SIAH2) is a RING-finger E3 ligase that serves as a key regulator of cellular responses to hypoxia and various stress signals (UniProt, Wikipedia). By mediating the polyubiquitination and subsequent proteasomal degradation of substrates like prolyl hydroxylases (PHDs) and Sprouty2, SIAH2 facilitates the stabilization of hypoxia-inducible factor 1-alpha (HIF-1α) and the activation of the Ras/MAPK signaling pathway (Cell, PNAS). These activities make SIAH2 a significant driver of tumorigenesis, metastasis, and chemoresistance in several cancers, including prostate, breast, and melanoma (NIH, PubMed). Consequently, SIAH2 is considered a high-value therapeutic target, with small molecule inhibitors like RLS-12 and Vitamin K3 (Menadione) under investigation to block its ligase activity or substrate interactions (NIH, PubMed). Beyond its role in cancer, SIAH2 is involved in regulating circadian rhythms and lipid metabolism, particularly in a sex-dimorphic manner, which presents both therapeutic opportunities and potential safety challenges (NIH). The protein's ability to modulate multiple signaling axes depending on the cellular context underscores its complexity as a drug target. Ongoing research aims to develop more selective inhibitors to minimize potential side effects related to its physiological roles in stress adaptation.

Other names

Seven in absentia homolog 2hSiah2Siah E3 ubiquitin protein ligase 2Seven in absentia homolog 2 (Drosophila)

Inhibition of E3 ubiquitin ligase activity and substrate degradation (NIH, PubMed)