Von Hippel–Lindau tumor suppressor (VHL)

The Von Hippel–Lindau (VHL) tumor suppressor is a multi-functional protein that primarily functions as the substrate-recognition subunit of an E3 ubiquitin ligase complex known as CRL2-VHL [1]. Under normoxic conditions, VHL identifies and binds to hydroxylated hypoxia-inducible factors (HIF-1α and HIF-2α), marking them for rapid proteasomal degradation and thereby preventing the activation of the cellular hypoxia response [2, 3]. Loss of VHL function, either through germline mutations in VHL syndrome or somatic mutations in sporadic cancers, leads to the constitutive stabilization of HIF, which drives pathological angiogenesis and the development of clear cell renal cell carcinoma (ccRCC) [4, 5]. \n\nIn the therapeutic landscape, VHL is targeted indirectly by HIF-2α inhibitors like belzutifan to manage tumors associated with VHL disease [6]. Furthermore, VHL-binding ligands have become essential components in the design of Proteolysis Targeting Chimeras (PROTACs), where they are used to hijack VHL's E3 ligase activity to selectively degrade non-native pathogenic proteins [7]. This dual role as both a genetic driver of disease and a versatile tool for targeted protein degradation makes VHL a high-priority focus for biotechnology and clinical research [7, 8]. \n\nCitations: [1] UniProt Consortium (2023) P40337; [2] Maxwell, P. H., et al. (1999) Nature 399(6733):271-275; [3] Ivan, M., et al. (2001) Science 292(5516):464-468; [4] Kaelin, W. G. (2008) Annual Review of Pathology 3:179-193; [5] Gossage, L., et al. (2015) Nature Reviews Cancer 15(1):55-64; [6] FDA (2021) 'FDA approves belzutifan for von Hippel-Lindau disease'; [7] Bondeson, D. P., et al. (2015) Nature Chemical Biology 11(8):611-617; [8] Galdeano, C., et al. (2014) Journal of Medicinal Chemistry 57(20):8657-8663.

Other names

pVHLVon Hippel-Lindau disease tumor suppressorProtein G7HRCA1RCA1Elongin binding protein

Functions as the substrate-recognition component of the CRL2-VHL E3 ubiquitin ligase complex to target HIF-alpha for degradation; also targeted via PROTAC ligands to recruit the ligase for neo-substrate degradation.