Von Hippel-Lindau tumor suppressor (VHL) (VHL)

The Von Hippel-Lindau (VHL) tumor suppressor is a critical protein that functions as the substrate recognition component of the CRL2-VHL E3 ubiquitin ligase complex (UniProt P40337). Its primary biological role is the oxygen-dependent regulation of hypoxia-inducible factors (HIF-1α and HIF-2α); under normoxic conditions, VHL binds to prolyl-hydroxylated HIF, leading to its polyubiquitination and proteasomal degradation (Maxwell et al., 1999, Nature). Mutations in the VHL gene result in the constitutive stabilization of HIF, which drives the expression of pro-angiogenic factors like VEGF, leading to Von Hippel-Lindau syndrome and clear cell renal cell carcinoma (Gossage et al., 2015, Nature Reviews Cancer). In pharmacology, VHL is a cornerstone of targeted protein degradation (TPD) technology, where VHL-binding ligands are incorporated into Proteolysis Targeting Chimeras (PROTACs) to hijack the ligase for the degradation of diverse therapeutic targets (Bondeson et al., 2015, Nature Chemical Biology). While VHL itself is often the 'machinery' rather than the direct inhibitory target, drugs like Belzutifan are specifically approved to treat tumors arising from VHL deficiency by targeting the downstream effector HIF-2α (FDA, 2021).

Other names

pVHLVHL1HRCA1RCA1Von Hippel-Lindau E3 ubiquitin ligase

VHL acts as the substrate-binding subunit of a Cullin-2-based E3 ubiquitin ligase complex. It recognizes and binds to hydroxylated proline residues on target proteins, most notably HIF-alpha subunits, facilitating their ubiquitination (Kaelin, 2008, Nature Reviews Cancer). In PROTAC technology, a bifunctional molecule recruits VHL to a specific protein of interest, bringing the E3 ligase into proximity to induce neo-substrate ubiquitination and degradation (Bondeson et al., 2015, Nature Chemical Biology).