Summary: This study investigates the role of the E3 ubiquitin ligase SCF (composed of Skp1, Cul1, and the F-box protein cyclin F) in linking AKT signaling to cell-cycle progression. The researchers demonstrate that cyclin F, an F-box protein whose expression fluctuates with the cell cycle, is phosphorylated by the oncogenic kinase AKT. This phosphorylation enhances cyclin F's stability and promotes its incorporation into active SCF E3 ligase complexes. Crucially, mutations in cyclin F that prevent AKT phosphorylation impair cell-cycle entry, suggesting that cyclin F acts as a conduit for mitogen signaling via AKT to the cell-cycle machinery, with potential relevance for cancer proliferation.

Summary: This review examines Cullin-RING ubiquitin ligases (CRLs) as dynamic platforms for target-specific ubiquitylation, building upon the initial F-box hypothesis for CUL1-based CRLs. It highlights the expansion of this system to a superfamily with over 200 human substrate-binding receptors and discusses regulatory circuits that control CRL activation and substrate ubiquitylation. The paper reviews molecular principles, allosteric and conformational mechanisms governing substrate timing and ubiquitylation, and the role of substrate receptor interchange in protein turnover and cellular decision-making, also noting CRLs as targets for therapeutic small molecules.

Summary: This study investigates the formation of E3-E3 super-assemblies between neddylated Cullin-RING ligases (CRLs), specifically the SCF family, and RBR-type E3 ligases like ARIH1. Using activity-based chemical probes and cryo-EM, the researchers visualized a novel ubiquitylation mechanism where ARIH1, after receiving ubiquitin from an E2 enzyme, transfers it to substrates bound by SCF complexes via F-box proteins. This E3-E3 assembly mechanism allows ubiquitylation of substrates incompatible with conventional RING E3-only mechanisms, suggesting a widespread role in protein ubiquitylation.

Summary: This review summarizes the structure and functions of Cullin-RING ubiquitin ligases (CRLs) in regulating cell cycle progression, highlighting that all eight CRL family members, including CRL1 (SCF), are involved in this process. It focuses on how CRLs target key cell cycle proteins for degradation or functional alteration to control progression through cell cycle phases and discusses the cooperative roles of CRLs with the APC/C ligase complex.

Summary: This paper reviews the critical role of the ubiquitin-proteasome system, particularly the Skp/cullin/F-box-containing (CRL) and anaphase-promoting complex/cyclosome (APC/C) E3 ligase families, in regulating cell division and maintaining genome integrity. It highlights that ubiquitylation is central to the cell cycle oscillator and genome maintenance, and also involved in various peripheral cell cycle-related processes, indicating a broad but complex regulatory landscape.

Summary: This review examines Cullin-2 based E3 ubiquitin ligase complexes, which are crucial for protein turnover via the 26S proteasome. It details the composition, structure, and regulation of these complexes, highlighting various substrate recognition receptors like VHL, Lrr-1, and Fem1b, and discusses their roles in cancer, germline differentiation, and viral defense, as well as potential anti-cancer therapeutic strategies.

Summary: This review focuses on Cullin-RING ubiquitin ligases (CRLs), the largest class of ubiquitin ligases, which regulate critical cellular processes including the cell cycle. CRLs are multisubunit complexes comprising a cullin, a RING H2 protein, a substrate-recognition subunit (SRS), and an adaptor. The review highlights the diversity of CRL classes, each formed by different cullins, adaptors, and SRSs, and discusses common regulatory mechanisms such as neddylation/deneddylation by the COP9 Signalosome (CSN), inhibitory binding by CAND1, and CRL dimerization, as well as cycles of activation and inactivation that switch substrate-recognition subunits.

Summary: This review examines SCF-type E3 ubiquitin ligases, which utilize F-box proteins to target substrates for degradation via the ubiquitin-proteasome pathway, with a focus on their roles in cancer development. It highlights specific F-box proteins like SKP2, often overexpressed and promoting cancer by degrading tumor suppressors, and FBXW7, frequently mutated and acting as a tumor suppressor by degrading oncogenic proteins. The review also discusses other F-box proteins involved in cancer-related processes such as cell cycle control, epigenetic regulation, and DNA-damage responses, positioning SKP2 as a potential drug target and FBXW7 as a biomarker.

Summary: This review focuses on the FBXL subfamily of F-box proteins, which are substrate-recruiting subunits of SCF-type E3 ubiquitin ligases. It highlights that while the 22 members of the FBXL family possess similar leucine-rich repeat (LRR) domains for substrate recruitment, the mechanisms by which they achieve their individual specificities remain unclear, and the review aims to explore these differences in detail.

Summary: This study investigated the mechanism by which cullin-RING E3 ligases position substrates for ubiquitination, focusing on nine substrate binding proteins (e.g., Skp2, Fbw7, Cdc4, pVHL) that interact with both substrates and E3 ligase modules. Using simulations, the researchers found that a flexible inter-domain linker, containing a conserved proline, acts as a hinge to optimally orient the substrate-binding domain for ubiquitin transfer. This linker flexibility, which can be allosterically regulated by binding events, provides a conformational control mechanism for substrate ubiquitination and polyubiquitination.

Summary: This review discusses proteomic technologies for identifying targets of cullin-RING (CRL) E3 ubiquitin ligases, which utilize F-box proteins as substrate-specific adaptors. It compares these proteomic approaches with genetic methods and highlights their importance for advancing the understanding of CRL biology and substrate identification.

Summary: This review discusses the ubiquitin-proteasome system as a therapeutic target, with a particular focus on Cullin-RING (CRL) E3 ubiquitin ligases due to their significant roles in biological processes and diseases like cancer. It details the assembly of CRL complexes, which involves substrate receptors, adaptors, Cullin scaffolds, and RING-box proteins, and reviews the current landscape of small-molecule inhibitors and modulators of CRL activity, including structural information on CRL components and complexes.

Summary: This paper reviews the involvement of Cullin-RING ligases (CRLs) in the response of cancer cells to ionizing radiation (IR) treatment, highlighting their crucial roles in cell cycle control, hypoxia signaling, reactive oxygen species clearance, and DNA repair, which are pivotal factors in cancer and normal tissue responses to IR. It discusses how drugs targeting the ubiquitin-proteasome system, particularly CRLs, are being explored in clinical trials to improve radiotherapy efficacy and suggests therapeutic approaches to target CRLs in the clinic.

Summary: This review focuses on the SCF complex, a key ubiquitin ligase in eukaryotes, which plays a crucial role in targeting regulatory proteins for degradation by the 26S proteasome. It highlights protein degradation as a mechanism for modulating protein abundance and switching cellular regulatory states, with ubiquitination by ligases controlling the specificity and timing of substrate marking.

Summary: This review focuses on the emerging roles of Cullin-RING ligases (CRLs) in regulating autophagy and the cross-talk between these two degradation systems. It highlights that CRLs are involved in ubiquitination and degradation of key regulators across various physiological processes, including cell cycle progression, and discusses the pathogenesis of diseases linked to the dysregulation of CRLs and autophagy, along with future research perspectives.

Summary: This review focuses on the crucial role of Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligases in regulating cell fate determination and differentiation during embryonic development, highlighting the ubiquitin proteasome system's importance in controlling developmental events through protein degradation.