Siah E3 ubiquitin-protein ligase 2 (SIAH2)

Siah E3 ubiquitin-protein ligase 2 (SIAH2) is an enzyme encoded by the SIAH2 gene and a member of the seven in absentia homolog family[1][2]. It acts as an E3 ubiquitin ligase, catalyzing the ubiquitination and subsequent proteasomal degradation of diverse protein substrates involved in transcription, apoptosis, cell signaling, protein homeostasis, and circadian rhythm regulation[2][4]. SIAH2 mediates key cellular processes including hypoxic response (by targeting prolyl hydroxylase domain proteins for degradation and regulating HIF-1α stability), as well as Wnt/β-catenin and Ras pathway modulation[1][2][4]. Dysregulation of SIAH2 is implicated in cancer progression, tumor suppression, neurodegenerative disorders, and other diseases, making it a potential therapeutic target. There are currently no clinically approved drugs specifically targeting SIAH2, but rational design of peptide-mimetic inhibitors has demonstrated feasibility in preclinical models[3].

Other names

Seven in absentia homolog 2SIAH2_HUMANSiah2

Inhibition of Siah2 leads to stabilization of substrates (e.g., PHD3), increased degradation of HIF-1α, and interference with downstream signaling pathways such as Erk and HIF signaling[3]. Blockade of protein–protein interactions responsible for substrate ubiquitination and proteasomal degradation[3].