E3 ubiquitin ligase Fbw7 negatively regulates granulocytic differentiation by targeting G-CSFR for degradation
Open accessAbstract
Tight control between activation and attenuation of granulocyte colony stimulating factor receptor (G-CSFR) signaling is essential to regulate survival, proliferation and differentiation of myeloid progenitor cells. Previous studies demonstrated negative regulation of G-CSFR through endosomal-lysosomal routing and ubiquitin-proteasome mediated degradation. However, very few E3 ubiquitin ligases are known to target G-CSFR for ubiquitin-proteasome pathway. Here we identified F-box and WD repeat domain-containing 7 (Fbw7), a substrate recognizing component of Skp-Cullin-F box (SCF) E3 ubiquitin Ligase physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation. Our data shows that Fbw7 also interacts with and degrades G-CSFR-T718 (a truncated mutant of G-CSFR found in severe congenital neutropenia/acute myeloid leukemia (SCN/AML patients)) though at a quite slower rate compared to G-CSFR. We further show that glycogen synthase kinase 3 beta (GSK3β), like Fbw7 also targets G-CSFR and G-CSFR-T718 for degradation; however, Fbw7 and GSK3β are interdependent in targeting G-CSFR/G-CSFR-T718 for degradation because they are unable to degrade G-CSFR individually when either of them is knocked down. We further show that Fbw7 mediated downregulation of G-CSFR inhibits signal transducer and activator of transcription 3 (STAT3) phosphorylation which is required for G-CSF dependent granulocytic differentiation. In addition, our data also shows that inhibition of Fbw7 restores G-CSFR signaling leading to enhanced STAT3 activity resulting in massive granulocytic differentiation. These data indicate that Fbw7 together with GSK3β negatively regulates G-CSFR expression and its downstream signaling.
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FBW7 is the substrate recognition motif of multimeric E3 ligase SCF-FBW7 which binds to substrates by recognizing phosphorylated motifs via its WD40 repeat regions.
“F-box protein FBW7 is the substrate recognition motif of multimeric E3 ligase SCF-FBW7 (SKP-cullin-Fbox) which binds to substrates by recognizing phosphorylated motifs (phosphodegron motif) via its WD40 repeat regions (14,15).”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [15]
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- Authors
- Lochab, S., Pal, P., Kapoor, I., Kanaujiya, J. K., Sanyal, S., Behre, G., & Trivedi, A. K.
- Affiliations
- Central Drug Research Institute (IN)
- University Hospital Leipzig (DE)
- Corresponding author
- Trivedi, Arun Kumar
- ORCID
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 1833
- Issue
- 12
- Pages
- 2639-2652
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2002298463
- Cited by
- 35
- References
- 48
- Citations by year
- 2024: 7 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 5 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 4
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Biotechnology, India (GAP0068)
- Council of Scientific and industrial Research, CSIR (ASTHI-BSC0201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- FBXW7, granulocytic differentiation, ubiquitin-proteasome degradation, SCF ubiquitin ligase, GSK3β, STAT3 phosphorylation, severe congenital neutropenia, acute myeloid leukemia, G-CSF signaling, myeloid progenitor cells, protein degradation
- MeSH terms
- Glycogen Synthase Kinase 3 beta, F-Box-WD Repeat-Containing Protein 7, Animals, Cell Differentiation, Cell Line, Granulocytes, Humans, Kinetics, Protein Binding, Receptors, Granulocyte Colony-Stimulating Factor, Cell Cycle Proteins, Ubiquitin, Glycogen Synthase Kinase 3, Ubiquitin-Protein Ligases, F-Box Proteins, Proteasome Endopeptidase Complex, Mutant Proteins, STAT3 Transcription Factor, Mice, Gene Knockdown Techniques, Proteolysis
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