- FBW7 (F-box and WD repeat domain-containing 7), also known as FBXW7, is a critical tumor suppressor protein that functions as the substrate recognition component of the SCF (SKP1-CUL1-F-box) ubiquitin ligase complex. This protein plays a central role in cell cycle regulation, differentiation, and growth control by targeting multiple oncoproteins for degradation.
- The structure of FBW7 is highly specialized for its function. It contains an F-box domain that mediates its interaction with SKP1 and the rest of the SCF complex, and eight WD40 repeats that form a β-propeller structure responsible for substrate recognition. This structural arrangement allows FBW7 to specifically recognize phosphorylated degrons in its target proteins.
- FBW7 operates through a precisely regulated mechanism of substrate recognition. It primarily recognizes a conserved phospho-degron motif (CPD) in its target proteins, which typically must be phosphorylated by specific kinases such as GSK3β. This requirement for phosphorylation adds an additional layer of regulation to protein degradation and allows for signal-dependent control of target protein levels.
- The list of FBW7 substrates includes numerous proteins crucial for cell growth and division. Key targets include c-Myc, cyclin E, Notch, c-Jun, and MCL1, among others. By controlling the levels of these important regulatory proteins, FBW7 helps maintain proper cell cycle progression and prevents uncontrolled cell growth.
- In normal cells, FBW7 exists in three isoforms (α, β, and γ) with distinct subcellular localizations and functions. The α isoform is nucleoplasmic, β is cytoplasmic, and γ is nucleolar. This differential localization allows FBW7 to regulate different pools of substrate proteins and respond to various cellular signals.
- The importance of FBW7 in cancer suppression is highlighted by its frequent mutation or deletion in various human cancers. Loss of FBW7 function leads to the accumulation of its oncogenic substrates, promoting cell proliferation, survival, and genomic instability. FBW7 mutations are particularly common in T-cell acute lymphoblastic leukemia, colon cancer, and cholangiocarcinoma.
- Beyond cancer, FBW7 plays crucial roles in development and stem cell maintenance. It regulates the balance between self-renewal and differentiation in various stem cell populations. Disruption of FBW7 function can lead to developmental abnormalities and affect tissue homeostasis.
- The regulation of FBW7 itself occurs at multiple levels, including transcriptional control, post-translational modifications, and protein-protein interactions. Its activity can be modulated by various cellular signals, allowing for dynamic control of substrate degradation in response to changing cellular conditions.
- Recent research has revealed new functions of FBW7 in cellular metabolism, stress responses, and DNA damage repair. These discoveries highlight the broader role of FBW7 in maintaining cellular homeostasis beyond its classical function in cell cycle regulation.
- Understanding FBW7 function has important therapeutic implications. Strategies to restore FBW7 function in cancers where it is lost, or to exploit FBW7-dependent degradation pathways, represent promising therapeutic approaches. Additionally, FBW7 status can serve as a biomarker for predicting response to certain cancer therapies.
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