Specificity of the ubiquitin proteasome system is controlled by ubiquitin E3 ligases, including their major representatives, the multisubunit cullin-RING ubiquitin (Ub) ligases (CRLs). More than 200 different CRLs are divided into seven families according to their cullin scaffolding proteins (CUL1–7) around which they are assembled. Research over two decades has revealed that different CRL families are specialized to fulfill specific cellular functions. Whereas many CUL1-based CRLs (CRL1s) ubiquitylate cell cycle regulators, CRL4 complexes often associate with chromatin to control DNA metabolism. Based on studies about differentiation programs of mesenchymal stem cells (MSCs), including myogenesis, neurogenesis, chondrogenesis, osteogenesis and adipogenesis, we propose here that CRL3 complexes evolved to fulfill a pivotal role in mammalian cell differentiation.

泛素蛋白酶体系统的特异性受泛素E3连接酶（包括其主要代表，多亚基cullin-RING泛素（Ub）连接酶（CRL））控制。根据200种不同的CRL，根据其围绕的cullin支架蛋白（CUL1–7）分为七个家族。二十年来的研究表明，不同的CRL系列专门用于实现特定的细胞功能。许多基于CUL1的CRL（CRL1）泛素化细胞周期调节剂，而CRL4复合物通常与染色质结合以控制DNA代谢。基于对间充质干细胞（MSCs）分化程序的研究，包括肌生成，神经生成，软骨生成，成骨和成脂，