Cul2

Cullin-2 (CUL2) is a core component of the cullin-RING ubiquitin ligase complex CRL2, a modular E3 ubiquitin ligase that tags specific proteins for proteasomal degradation. CUL2 acts as a scaffold that organizes the CRL2 core, recruiting the RING finger protein RBX1 (ROC1) and the adaptor proteins of the elongin B and C complex (ELOB and ELOC). Substrate specificity is conferred by adaptor proteins that contain a SOCS box or related motifs, such as the von Hippel-Lindau (VHL) tumor suppressor and other SOCS-family members. These receptors bind target proteins and present them to the CRL2 core for ubiquitination.

In its best-characterized function, CRL2–VHL targets hypoxia-inducible factor 1 alpha (HIF-1α) for ubiquitination and degradation under normoxic conditions, thereby regulating the cellular response to oxygen availability. Under hypoxic conditions, HIF-1α is stabilized and activates transcription of genes involved in angiogenesis, metabolism, and survival. Beyond HIF-1α, CRL2–SOCS complexes regulate diverse pathways, including cytokine signaling, receptor turnover, and cell cycle control, by promoting degradation of signaling molecules and transcriptional regulators.

Alterations in CRL2 components or their adapters have been linked to disease. Inactivation of VHL or disruption of CRL2 function contributes to tumorigenesis, most notably in clear cell renal carcinoma, where HIF-driven transcription promotes angiogenesis and metabolic adaptation. Given its central role in targeted protein turnover, CUL2 remains a focus of research in oncology and in studies of ubiquitin-mediated regulation of cellular signaling.