Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases

Abstract

The SCF (SKP1 (S-phase-kinase-associated protein 1), Cullin-1, F-box protein) E3 ubiquitin ligases, the founding member of Cullin-RING ligases (CRLs), are the largest family of E3 ubiquitin ligases in mammals. Each individual SCF E3 ligase consists of one adaptor protein SKP1, one scaffold protein cullin-1 (the first family member of the eight cullins), one F-box protein out of 69 family members, and one out of two RING (Really Interesting New Gene) family proteins RBX1/ROC1 or RBX2/ROC2/SAG/RNF7. Various combinations of these four components construct a large number of SCF E3s that promote the degradation of many key regulatory proteins in cell-context, temporally, and spatially dependent manners, thus controlling precisely numerous important cellular processes, including cell cycle progression, apoptosis, gene transcription, signal transduction, DNA replication, maintenance of genome integrity, and tumorigenesis. To understand how the SCF E3 ligases regulate these cellular processes and embryonic development under in vivo physiological conditions, a number of mouse models with transgenic (Tg) expression or targeted deletion of components of SCF have been established and characterized. In this review, we will provide a brief introduction to the ubiquitin-proteasome system (UPS) and the SCF E3 ubiquitin ligases, followed by a comprehensive overview on the existing Tg and knockout (KO) mouse models of the SCF E3s, and discuss the role of each component in mouse embryogenesis, cell proliferation, apoptosis, carcinogenesis, as well as other pathogenic processes associated with human diseases. We will end with a brief discussion on the future directions of this research area and the potential applications of the knowledge gained to more effective therapeutic interventions of human diseases.

FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4

“…Having established XRCC4-S325/326-dependent binding between FBXW7 and XRCC4 (Figure 3C), which is consistent with the notion that phosphorylation of substrate binding motifs is a prerequisite for substrate recognition by an F-box protein (Zhou et al, 2013), we next determined if XRCC4 polyubiquitylation is also dependent on S325/326 phosphorylation. Indeed, polyubiquitylation promoted by UBC13 was observed only in response to wild type XRCC4, with no or substantially reduced polyubiquitylation in the S325/326A mutant (Figures 4A and S4A).…”

The Neddylation-Cullin 2-RBX1 E3 Ligase Axis Targets Tumor Suppressor RhoB for Degradation in Liver Cancer

“…The core structure of CRL is a complex of cullin-RING finger proteins (RBX1 or RBX2) in which one of seven cullin family members interacts with either RBX1 or RBX2 to activate CRL (50,55). Unlike other cullin family members whose substrates have been frequently identified (56), only a few substrates of cullin 2, such as HIF-1␣ (57,58), have been revealed. In this study, we defined RhoB as a new substrate of cullin 2.…”

SAG/RBX2 E3 ligase complexes with UBCH10 and UBE2S E2s to ubiquitylate β-TrCP1 via K11-linkage for degradation

“…Protein ubiquitylation is a post-translational modification, that via modulating protein stability, activity, or localization1 regulates many cellular pathways including proinflammatory signaling, DNA damage response, and apoptosis23. Protein ubiquitylation is catalyzed by an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase, that is responsible for substrate recognition4, and catalyzes the transfer of ubiquitin directly from the E2 to the substrate5.…”