Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses
Open accessAbstract
It currently is believed that vitamin A, retinol, functions through active metabolites: the visual chromophore 11- cis -retinal, and retinoic acids, which regulate gene transcription. Retinol circulates in blood bound to retinol-binding protein (RBP) and is transported into cells by a membrane protein termed “stimulated by retinoic acid 6” (STRA6). We show here that STRA6 not only is a vitamin A transporter but also is a cell-surface signaling receptor activated by the RBP–retinol complex. Association of RBP-retinol with STRA6 triggers tyrosine phosphorylation, resulting in recruitment and activation of JAK2 and the transcription factor STAT5. The RBP–retinol/STRA6/JAK2/STAT5 signaling cascade induces the expression of STAT target genes, including suppressor of cytokine signaling 3 ( SOCS3 ), which inhibits insulin signaling, and peroxisome proliferator-activated receptor gamma ( PPARγ ), which enhances lipid accumulation. These observations establish that the parental vitamin A molecule is a transcriptional regulator in its own right, reveal that the scope of biological functions of the vitamin is broader than previously suspected, and provide a rationale for understanding how RBP and retinol regulate energy homeostasis and insulin responses.
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Vitamin A/retinol activates the Janus kinase/STAT5 signaling pathway.
“Finally, vitamin A/retinol proved recently to be active and to activate the Janus kinase/STAT5 signaling pathway.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [126]
This nuclear integration involves mainly phosphorylation processes that influence their DNA recruitment and the timing of the sequential recruitment of the different classes of coregulators, as well as the stability of the phosphorylated proteins.
“This nuclear integration involves mainly phosphorylation processes that infl uence their DNA recruitment and the timing of the sequential recruitment of the different classes of coregulators, as well as the stability of the phosphorylated proteins.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [126]
RA- and retinol-induced kinases have been reported to cross talk with the transcriptional activity of RARs and other transcription factors.
“In line with this concept, the RA-and retinol-induced kinases have been reported to cross talk with the transcriptional activity of RARs and other transcription factors.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [126]
Retinol associated to RBP and bound to the cell surface signaling receptor Stra6 was found to activate the JAK/STAT5 signaling cascade.
“Indeed retinol that was associated to the “retinol-binding protein (RBP)” and that was bound to the cell surface signaling receptor stimulated by retinoic acid 6 (Stra6) was found to activate the Janus kinases (JAK)/signal transducer and activator of transcription 5 (STAT5) signaling cascade ( 126-128 ) ( Fig. 5B ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [126]
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Vitamin A and retinoid signaling: genomic and nongenomic effects
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Liver Retinol Transporter and Receptor for Serum Retinol-binding Protein (RBP4)
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- Authors
- Berry, D. C., Jin, H., Majumdar, A., & Noy, N.
- Affiliations
- Case Western Reserve University (US)
- Departments of aPharmacology and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-02-23
- Volume
- 108
- Issue
- 11
- Pages
- 4340-4345
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3060239
- OpenAlex
- W2057249117
- Cited by
- 204
- References
- 9
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 7 · 2023: 16 · 2022: 15 · 2021: 21 · 2020: 9 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 13 · 2015: 21 · 2014: 19 · 2013: 15 · 2012: 22
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Case Western Reserve University
- National Institutes of Health (DK 59630, CA107013, DK060684)
- National Cancer Institute (CA107013, R01CA107013)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 59630, DK060684, DK073195T32, U24DK059630, R01DK060684, KO1-DK077915, K01DK077915)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- vitamin A, retinol, retinol-binding protein, STRA6, JAK2, STAT5, tyrosine phosphorylation, SOCS3, PPARγ, insulin signaling, lipid accumulation, energy homeostasis, transcriptional regulation
- MeSH terms
- Animals, Enzyme Activation, Gene Expression Regulation, Humans, Insulin, Membrane Proteins, Models, Biological, Phosphorylation, Protein Binding, Retinol-Binding Proteins, Triglycerides, Vitamin A, Signal Transduction, Transcriptional Activation, STAT5 Transcription Factor, Mice, Janus Kinase 2, Hep G2 Cells
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