Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mammalian Cell Differentiation.

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.