CUL2 (cullin 2) functions as a core scaffolding component of ElonginB/C-CUL2-SOCS-box protein (ECS) E3 ubiquitin ligase complexes that mediate ubiquitination and proteasomal degradation of target proteins 12. CUL2 serves as a rigid scaffold positioning substrates and E2 ubiquitin-conjugating enzymes to facilitate catalysis 34. E3 ligase activity requires neddylation of CUL2 and is inhibited when deneddylated CUL2 associates with TIP120A/CAND1 45. Substrate specificity depends on the substrate recognition component; notably, ECS(VHL) ubiquitinates hypoxia-inducible factor (HIF) 36. Multiple ECS complexes participate in the DesCEND pathway, recognizing C-terminal degrons to target proteins for degradation 278. CUL2(FEM1B) mediates the reductive stress response by ubiquitinating FNIP1 during conditions of depleted ROS, restoring mitochondrial activity and redox homeostasis 91011. CUL2(LRR1) ubiquitinates MCM7 to promote CMG replisome disassembly during S-phase 12. Clinical relevance includes VHL disease, where VHL mutations disrupt the CUL2-containing complex, leading to HIF accumulation and vascular tumors 13.