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Noa Noy - One of the best experts on this subject based on the ideXlab platform.
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the retinol binding protein receptor STRA6 regulates diurnal insulin responses
Journal of Biological Chemistry, 2017Co-Authors: Christy Gliniak, Mark J Brown, Noa NoyAbstract:It has long been appreciated that insulin action is closely tied to circadian rhythms. However, the mechanisms that dictate diurnal insulin sensitivity in metabolic tissues are not well understood. Retinol-binding protein 4 (RBP4) has been implicated as a driver of insulin resistance in rodents and humans, and it has become an attractive drug target in type II diabetes. RBP4 is synthesized primarily in the liver where it binds retinol and transports it to tissues throughout the body. The retinol-RBP4 complex (holo-RBP) can be recognized by a cell-surface receptor known as stimulated by retinoic acid 6 (STRA6), which transports retinol into cells. Coupled to retinol transport, holo-RBP can activate STRA6-driven Janus kinase (JAK) signaling and downstream induction of signal transducer and activator of transcription (STAT) target genes. STRA6 signaling in white adipose tissue has been shown to inhibit insulin receptor responses. Here, we examined diurnal rhythmicity of the RBP4/STRA6 signaling axis and investigated whether STRA6 is necessary for diurnal variations in insulin sensitivity. We show that adipose tissue STRA6 undergoes circadian patterning driven in part by the nuclear transcription factor REV-ERBα. Furthermore, STRA6 is necessary for diurnal rhythmicity of insulin action and JAK/STAT signaling in adipose tissue. These findings establish that holo-RBP and its receptor STRA6 are potent regulators of diurnal insulin responses and suggest that the holo-RBP/STRA6 signaling axis may represent a novel therapeutic target in type II diabetes.
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RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and Mediates High-Fat Diet-Induced Colon Carcinogenesis
Stem cell reports, 2017Co-Authors: Sheelarani Karunanithi, Liraz Levi, Jennifer Devecchio, George Karagkounis, Ofer Reizes, Justin D. Lathia, Matthew F. Kalady, Noa NoyAbstract:Summary The transmembrane protein, STRA6, functions as a vitamin A transporter and a cytokine receptor when activated by vitamin A-bound serum retinol binding protein 4 (RBP4). STRA6 activation transduces a JAK2-STAT3 signaling cascade and promotes tumorigenesis in a xenograft mouse model of colon cancer. We show here that RBP4 and STRA6 expression is associated with poor oncologic prognosis. Downregulating STRA6 or RBP4 in colon cancer cells decreased the fraction of cancer stem cells and their sphere and tumor initiation frequency. Furthermore, we show that high-fat diet (HFD) increases LGR5 expression and promotes tumor growth in a xenograft model independent of obesity. HFD increased STRA6 levels, and downregulation of STRA6 delays and impairs tumor initiation, tumor growth, and expression of stemness markers. Together, these data demonstrate a key role of STRA6 and RBP4 in the maintenance of colon cancer self-renewal and that this pathway is an important link through which consumption of HFD contributes to colon carcinogenesis.
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Vitamin A Transport and Cell Signaling by the Retinol-Binding Protein Receptor STRA6
Sub-cellular biochemistry, 2016Co-Authors: Noa NoyAbstract:Vitamin A, retinol, circulates in blood bound to retinol binding protein (RBP). In some tissues, the retinol-RBP complex (holo-RBP) is recognized by a membrane receptor, termed STRA6, which mediates uptake of retinol into cells. Recent studies have revealed that, in addition to serving as a retinol transporter, STRA6 is a ligand-activated cell surface signaling receptor that, upon binding of holo-RBP activates JAK/STAT signaling, culminating in the induction of STAT target genes. It has further been shown that retinol transport and cell signaling by STRA6 are critically interdependent and that both are coupled to intracellular vitamin A metabolism. The molecular mechanism of action of STRA6 and its associated machinery is beginning to be revealed, but further work is needed to identify and characterize the complete range of genes and associated signaling cascades that are regulated by STRA6 in different tissues. An understanding of STRA6 is clinically relevant, as for example, it has been shown to be hyper- activated in obese animals, leading to insulin resistance. A potential role for STRA6 in other pathologies, including cancer, awaits further investigation.
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Vitamin A in regulation of insulin responsiveness: mini review.
The Proceedings of the Nutrition Society, 2016Co-Authors: Noa NoyAbstract:Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP4) which, in turn, associates with another serum protein, transthyretin (TTR), to form a ternary retinol-RBP4-TTR complex. At some tissues, retinol-bound (holo-) RBP4 is recognised by a receptor termed stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. This mini-review summarises evidence demonstrating that, in addition to functioning as a retinol transporter, STRA6 is also a signalling receptor which is activated by holo-RBP4. The data show that STRA6-mediated retinol transport induces receptor phosphorylation, in turn activating a Janus kinases2/signal transducers and activators of transcription (STAT)3/5 cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signalling are inter-dependent, and both functions critically rely on intracellular retinol trafficking and metabolism. Hence, STRA6 couples 'sensing' of vitamin A homeostasis and metabolism to cell signalling, allowing it to control important biological functions. For example, by inducing the expression of the STAT target gene suppressor of cytokine signalling 3, STRA6 potently suppresses insulin responses. These observations provide a rationale for understanding the reports that elevation in serum levels of RBP4, often observed in obese mice and human subjects, causes insulin resistance. The observations indicate that the holo-RBP4 /STRA6 signalling cascade may comprise an important link through which obesity leads to insulin resistance and suggest that the pathway may be a novel target for treatment of metabolic diseases.
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holo retinol binding protein and its receptor STRA6 drive oncogenic transformation
Cancer Research, 2014Co-Authors: Daniel C Berry, Liraz Levi, Noa NoyAbstract:Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP). At some tissues, RBP is recognized by STRA6, a plasma membrane protein that serves a dual role: it transports retinol from extracellular RBP into cells and it transduces a signaling cascade mediated by the Janus kinase JAK2 and the transcription factors STAT3 and STAT5. We show here that expression of RBP and STRA6 is markedly upregulated in human breast and colon tumors, that holo-RBP/STRA6 signaling promotes oncogenic properties, and that STRA6 expression is critical for tumor formation by colon carcinoma cells in vivo. The holo-RBP/STRA6 pathway also efficiently induces fibroblasts to undergo oncogenic transformation rendering them highly tumorigenic. The data establish that holo-RBP and its receptor STRA6 are potent oncogenes and suggest that the pathway is a novel target for therapy of some human cancers.
Hui Sun - One of the best experts on this subject based on the ideXlab platform.
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How Free Retinol Behaves Differently from RBP-Bound Retinol in
2016Co-Authors: Rbp Receptor-mediated, Ming Zhong, Riki Kawaguchi, Miki Kassai, Vitamin A Uptake, Hui SunAbstract:Berry et al. claimed that holo-retinol-binding protein (holo-RBP) binds to STRA6 to trigger insulin resistance but does not contribute to retinol uptake from holo-RBP (1). These claims, based on improperly performed assays, contradict many studies on STRA6 (2–10) and the findings that apo-RBP, not holo-RBP, is elevated in cases of obesity and type 2 diabetes (11, 12). The claims of Berry et al. also contradict two independent studies published in Molecular and Cellular Biology showing that RBP’s role in insu-lin resistance is independent of STRA6 and retinol (13, 14). Properly formed retinol/RBP complex, a cell type that is con-firmed to express the STRA6 protein, and the ability to distinguish true intracellular uptake from nonspecific binding (e.g., nonspe-cific sticking of [3H]retinol or [3H]retinol/RBP to plastic or cell surfaces) are prerequisites in STRA6-dependent vitamin A uptake assays. It has been well established from numerous studies, includ-ing crystallographic studies, that retinol forms a 1:1 complex with RBP. However, Berry et al. performed all [3H]retinol uptake as-says by mixing free [3H]retinol with unlabeled holo-RBP and ap-plying this mixture without removing free [3H]retinol. Because [3H]retinol/RBP was not properly formed and no free [3H]retinol was removed, this assay is a free [3H]retinol diffusion assay, not an assay of STRA6-mediated [3H]retinol uptake from the [3H]reti-nol/RBP complex (Fig. 1). It has been known since the 1970s that retinyl ester bound to lipoproteins is an RBP-independent mechanism of delivering vi-tamin A (15). Since RBP knockout mice have primarily vision defects under vitamin A-sufficient conditions (16, 17), it is no
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To investigate the necessity of STRA6 upregulation in T cells during T cell immune responses.
PLoS ONE, 2013Co-Authors: Rafik Terra, Ming Zhong, Hui Sun, Xuehai Wang, Tania Charpentier, Alain Lamarre, Jianning Mao, Hongyu LuoAbstract:Our earlier study revealed that STRA6 (stimulated by retinoic acid gene 6) was up-regulated within 3 h of TCR stimulation. STRA6 is the high-affinity receptor for plasma retinol-binding protein (RBP) and mediates cellular vitamin A uptake. We generated STRA6 knockout (KO) mice to assess whether such up-regulation was critical for T-cell activation, differentiation and function. STRA6 KO mice under vitamin A sufficient conditions were fertile without apparent anomalies upon visual inspection. The size, cellularity and lymphocyte subpopulations of STRA6 KO thymus and spleen were comparable to those of their wild type (WT) controls. KO and WT T cells were similar in terms of TCR-stimulated proliferation in vitro and homeostatic expansion in vivo. Naive KO CD4 cells differentiated in vitro into Th1, Th2, Th17 as well as regulatory T cells in an analogous manner as their WT counterparts. In vivo experiments revealed that anti-viral immune responses to lymphocytic choriomeningitis virus in KO mice were comparable to those of WT controls. We also demonstrated that STRA6 KO and WT mice had similar glucose tolerance. Total vitamin A levels are dramatically lower in the eyes of KO mice as compared to those of WT mice, but the levels in other organs were not significantly affected after STRA6 deletion under vitamin A sufficient conditions, indicating that the eye is the mouse organ most sensitive to the loss of STRA6. Our results demonstrate that 1) in vitamin A sufficiency, the deletion of STRA6 in T cells does no affect the T-cell immune responses so-far tested, including those depend on STAT5 signaling; 2) STRA6-independent vitamin A uptake compensated the lack of STRA6 in lymphoid organs under vitamin A sufficient conditions in mice; 3) STRA6 is critical for vitamin A uptake in the eyes even in vitamin A sufficiency.
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Vitamin A transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein.
PloS one, 2013Co-Authors: Ming Zhong, Riki Kawaguchi, Mariam Ter-stepanian, Miki Kassai, Hui SunAbstract:Vitamin A and its derivatives (retinoids) play diverse and crucial functions from embryogenesis to adulthood and are used as therapeutic agents in human medicine for eye and skin diseases, infections and cancer. Plasma retinol binding protein (RBP) is the principal and specific vitamin A carrier in the blood and binds vitamin A at 1∶1 ratio. STRA6 is the high-affinity membrane receptor for RBP and mediates cellular vitamin A uptake. STRA6 null mice have severely depleted vitamin A reserves for vision and consequently have vision loss, even under vitamin A sufficient conditions. STRA6 null humans have a wide range of severe pathological phenotypes in many organs including the eye, brain, heart and lung. Known membrane transport mechanisms involve transmembrane pores that regulate the transport of the substrate (e.g., the gating of ion channels). STRA6 represents a new type of membrane receptor. How this receptor interacts with its transport substrate vitamin A and the functions of its nine transmembrane domains are still completely unknown. These questions are critical to understanding the molecular basis of STRA6′s activities and its regulation. We employ acute chemical modification to introduce chemical side chains to STRA6 in a site-specific manner. We found that modifications with specific chemicals at specific positions in or near the transmembrane domains of this receptor can almost completely suppress its vitamin A transport activity. These experiments provide the first evidence for the existence of a transmembrane pore, analogous to the pore of ion channels, for this new type of cell-surface receptor.
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Differential and Isomer-Specific Modulation of Vitamin A Transport and the Catalytic Activities of the RBP Receptor by Retinoids
The Journal of Membrane Biology, 2013Co-Authors: Riki Kawaguchi, Ming Zhong, Mariam Ter-stepanian, Miki Kassai, Hui SunAbstract:Retinoids are vitamin A derivatives with diverse biological functions. Both natural and artificial retinoids have been used as therapeutic reagents to treat human diseases, but not all retinoid actions are understood mechanistically. Plasma retinol binding protein (RBP) is the principal and specific carrier of vitamin A in the blood. STRA6 is the membrane receptor for RBP that mediates cellular vitamin A uptake. The effects of retinoids or related compounds on the receptor’s vitamin A uptake activity and its catalytic activities are not well understood. In this study, we dissected the membrane receptor-mediated vitamin A uptake mechanism using various retinoids. We show that a subset of retinoids strongly stimulates STRA6-mediated vitamin A release from holo-RBP. STRA6 also catalyzes the exchange of retinol in RBP with certain retinoids. The effect of retinoids on STRA6 is highly isomer-specific. This study provides unique insights into the RBP receptor’s mechanism and reveals that the vitamin A transport machinery can be a target of retinoid-based drugs.
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Effect of MTSEA-biotin modification on STRA6-mediated vitamin A uptake as measured by 3H-retinol uptake from 3H-retinol/RBP and HPLC analysis of retinyl esters.
2013Co-Authors: Ming Zhong, Riki Kawaguchi, Mariam Ter-stepanian, Miki Kassai, Hui SunAbstract:A. Positions of V320C and S385C in the transmembrane topology model of STRA6. Because MTSEA-biotin is membrane impermeable, the location of S385C close to the intracellular side of STRA6 makes it inaccessible to MTSEA-biotin from the extracellular side, while V320C is positioned on the boundary of membrane helix VI and extracellular domain and can be accessed by MTSEA-biotin from the extracellular side. B and C. Cell-free vitamin A uptake assays comparing the effect of MTSEA-biotin treatment on STRA6-WT (WT) and STRA6-S385C (S385C). B is 3H-retinol uptake assay from 3H-retinol/RBP. C is HPLC-based retinyl ester analysis of retinol uptake from holo-RBP. D and E. Live-cell vitamin A uptake assays comparing the effect of MTSEA-biotin treatment on STRA6-WT (WT) and STRA6-V320C (V320C). D is 3H-retinol uptake assay from 3H-retinol/RBP. E is HPLC-based retinyl ester analysis of retinol uptake from holo-RBP. In B and D, the amount of 3H-retinol associated with STRA6-WT without modification is defined as 100%. This activity reflects the binding of 3H-retinol/RBP to STRA6. In C and E, the activity of STRA6-WT with LRAT as measured by retinyl ester amount is defined as 100%. Grey bars, no treatment. Green bars, MTSEA-biotin treatment.
Daniel C Berry - One of the best experts on this subject based on the ideXlab platform.
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holo retinol binding protein and its receptor STRA6 drive oncogenic transformation
Cancer Research, 2014Co-Authors: Daniel C Berry, Liraz Levi, Noa NoyAbstract:Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP). At some tissues, RBP is recognized by STRA6, a plasma membrane protein that serves a dual role: it transports retinol from extracellular RBP into cells and it transduces a signaling cascade mediated by the Janus kinase JAK2 and the transcription factors STAT3 and STAT5. We show here that expression of RBP and STRA6 is markedly upregulated in human breast and colon tumors, that holo-RBP/STRA6 signaling promotes oncogenic properties, and that STRA6 expression is critical for tumor formation by colon carcinoma cells in vivo. The holo-RBP/STRA6 pathway also efficiently induces fibroblasts to undergo oncogenic transformation rendering them highly tumorigenic. The data establish that holo-RBP and its receptor STRA6 are potent oncogenes and suggest that the pathway is a novel target for therapy of some human cancers.
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Holo-Retinol–Binding Protein and Its Receptor STRA6 Drive Oncogenic Transformation
Cancer research, 2014Co-Authors: Daniel C Berry, Liraz Levi, Noa NoyAbstract:Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP). At some tissues, RBP is recognized by STRA6, a plasma membrane protein that serves a dual role: it transports retinol from extracellular RBP into cells and it transduces a signaling cascade mediated by the Janus kinase JAK2 and the transcription factors STAT3 and STAT5. We show here that expression of RBP and STRA6 is markedly upregulated in human breast and colon tumors, that holo-RBP/STRA6 signaling promotes oncogenic properties, and that STRA6 expression is critical for tumor formation by colon carcinoma cells in vivo. The holo-RBP/STRA6 pathway also efficiently induces fibroblasts to undergo oncogenic transformation rendering them highly tumorigenic. The data establish that holo-RBP and its receptor STRA6 are potent oncogenes and suggest that the pathway is a novel target for therapy of some human cancers.
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Oncogenic Transformation Binding Protein and Its Receptor STRA6 Drive - Holo-Retinol
2014Co-Authors: Daniel C Berry, Liraz Levi, Noa NoyAbstract:Abstract Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP). At some tissues, RBP isrecognizedbySTRA6,aplasmamembraneproteinthatservesadualrole:ittransportsretinolfromextracellularRBP into cells and it transduces a signaling cascade mediated by the Janus kinase JAK2 and the transcriptionfactors STAT3 and STAT5. We show here that expression of RBP and STRA6 is markedly upregulated in humanbreast and colon tumors, that holo-RBP/STRA6 signaling promotes oncogenic properties, and that STRA6expression is critical for tumor formation by colon carcinoma cells in vivo. The holo-RBP/STRA6 pathway alsoefficiently induces fibroblasts to undergo oncogenic transformation, rendering them highly tumorigenic. Thesedataestablishthatholo-RBPanditsreceptorSTRA6arepotentoncogenesandsuggestthatthepathwayisanoveltarget for therapy of some human cancers. Cancer Res; 74(21); 1–11. 2014 AACR. Introduction Vitamin A, retinol (ROH), is essential for multiple biologicfunctions both during embryonic development and in theadult. Many of the biologic activities of retinol are exerted byits active metabolite all-trans-retinoic acid (RA), which reg-ulates transcription by activating the nuclear receptors reti-noic acid receptors and PPARb/d (1, 2). Vitamin A is stored invarious tissues, including adipose tissue, lung, and retinalpigment epithelium in the eye, but its major storage site is inthe liver. ROH is secreted from storage pools into the circu-lation bound to serum retinol-binding protein (RBP). In turn,ROH-bound RBP (holo-RBP) associates in blood with anotherplasma protein, transthyretin (TTR), to form a holo-RBP–TTRcomplex that circulates at approximately 1:1 molar stoichio-metry under normal physiologic conditions (3, 4).ROH enters target cells from circulating holo-RBP by twodistinctmechanisms.Becauseofitslipophilicnature,itreadilydiffusesthroughtheplasmamembrane,aprocessthat,inmosttissues,accountsforthemajorfractionofvitaminAuptakebycells(4–7).ROHcanalsobetransportedintocellsbyanintegralplasma membrane protein termed Stimulated by RA 6(STRA6), which binds extracellular holo-RBP and transportsROH into cells (8). Although STRA6-mediated ROH uptake isnot necessary for maintaining adequate ROH supply in mosttissues, its contribution to ROH supply becomes significant incellsthatexpressaveryhighlevelofthereceptor,primarilytheretinal pigment epithelium (RPE) in the eye (7, 9).Our recent studies surprisingly revealed that, in addition toservingasavitaminAtransporter,STRA6isacytokinereceptor.We thus found that binding of holo-RBP triggers phosphory-lation of a tyrosine residue in the cytosolic domain of STRA6,resultinginrecruitmentandactivationoftheJanuskinaseJAK2and, in a cell-dependent manner, the transcription factorsSTAT3 or STAT5 (10, 11). Holo-RBP thus activates STRA6-mediated signaling that culminates in upregulation of STATtarget genes. Interestingly, the two functions of STRA6 werefound to be interdependent, i.e., STRA6-mediated ROH trans-port is required for activation of STRA6 signaling, and, viceversa, phosphorylation of STRA6 is essential for retinol trans-port mediated by the receptor (11). The observations furtherdemonstrated that STRA6 directly transfers ROH from extra-cellularRBPtocellularretinol-bindingprotein1(CRBP1),whichdirectlybindstoSTRA6,acceptsROH,anddissociatesfromthereceptor upon ligation (11). STRA6-mediated ROH uptake alsocritically requires the presence of lecithin:retinol acyl transfer-ase (LRAT), an enzyme that catalyzes the conversion of retinoltoitsstoragespeciesretinylesters.TransferofROHfromCRBP1to LRAT regenerates apo-CRBP1, enabling the binding proteinto reassociate with STRA6 and further promote ROH uptakeand STRA6 signaling (11). ROH metabolism by LRAT alsomaintains an inward directed ROH concentration gradient,necessary for continuing influx. Hence, STRA6 orchestrates amulticomponent "machinery" that couples vitamin A homeo-stasis and metabolism to activation of a signaling cascade.Importantly, the binding partner for RBP in blood, TTR,competes with STRA6 for holo-RBP and thus prevents holo-RBP from interacting with the receptor. Consequently, STRA6isonlyactiveeitherwhenholo-RBPlevelsinserumexceedthatofTTR,e.g.,inobeseanimals(5,12,13),orincellsthatexpressavery high level of the receptor, e.g., the RPE. Other physiologic
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The retinol esterifying enzyme LRAT supports cell signaling by retinol-binding protein and its receptor STRA6
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2013Co-Authors: Gurdeep Marwarha, Daniel C Berry, Colleen M. Croniger, Noa NoyAbstract:Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP). At some tissues, holo-RBP is recognized by a plasma membrane receptor termed STRA6, which serves a dual role: it mediates transport of retinol from RBP into cells, and it functions as a cytokine receptor that, on binding holo-RBP, activates JAK2/STAT5 signaling. As STAT target genes include SOCS3, an inhibitor of insulin receptor, holo-RBP suppresses insulin responses in STRA6-expressing cells. We have shown previously that the two functions of STRA6 are interdependent. These observations suggest factors that regulate STRA6-mediated retinol transport may also control STRA6-mediated cell signaling. One such factor is retinol metabolism, which enables cellular uptake of retinol by maintaining an inward-directed concentration gradient. We show here that lecithin:retinol acyl transferase (LRAT), which catalyzes esterification of retinol to its storage species retinyl esters, is necessary for activation of the STRA6/JAK2/STAT5 cascade by holo-RBP. In accordance, LRAT-null mice are protected from holo-RBP-induced suppression of insulin responses. Hence, STRA6 signaling, which requires STRA6-mediated retinol transport, is supported by LRAT-catalyzed retinol metabolism. The observations demonstrate that STRA6 regulates key cellular processes by coupling circulating holo-RBP levels and intracellular retinol metabolism to cell signaling.—Marwarha, G., Berry, D.C., Croniger, C.M., Noy, N. The retinol esterifying enzyme LRAT supports cell signaling by retinol-binding protein and its receptor STRA6.
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the STRA6 receptor is essential for retinol binding protein induced insulin resistance but not for maintaining vitamin a homeostasis in tissues other than the eye
Journal of Biological Chemistry, 2013Co-Authors: Daniel C Berry, Sheila M Obyrne, Hugues Jacobs, Gurdeep Marwarha, Aurore Gelypernot, David Desantis, Muriel Klopfenstein, Betty Feret, Christine Dennefeld, William S BlanerAbstract:The plasma membrane protein STRA6 is thought to mediate uptake of retinol from its blood carrier retinol-binding protein (RBP) into cells and to function as a surface receptor that, upon binding of holo-RBP, activates a JAK/STAT cascade. It was suggested that STRA6 signaling underlies insulin resistance induced by elevated serum levels of RBP in obese animals. To investigate these activities in vivo, we generated and analyzed STRA6-null mice. We show that the contribution of STRA6 to retinol uptake by tissues in vivo is small and that, with the exception of the eye, ablation of STRA6 has only a modest effect on retinoid homeostasis and does not impair physiological functions that critically depend on retinoic acid in the embryo or in the adult. However, ablation of STRA6 effectively protects mice from RBP-induced suppression of insulin signaling. Thus one biological function of STRA6 in tissues other than the eye appears to be the coupling of circulating holo-RBP levels to cell signaling, in turn regulating key processes such as insulin response. Background: STRA6 transports retinol into cells and activates cell signaling. Results: Ablation of STRA6 does not impair vitamin A homeostasis in tissues other than the eye but protects mice against RBP-induced insulin resistance. Conclusion: One major function of STRA6 is to control cell signaling. Significance: The data point at a new function for vitamin A and its blood carrier RBP.
Riki Kawaguchi - One of the best experts on this subject based on the ideXlab platform.
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Regulatory mechanism for the transmembrane receptor that mediates bidirectional vitamin A transport.
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Ming Zhong, Riki Kawaguchi, Miki Kassai, Brianna Costabile, Yuyan Tang, Guo Cheng, Bernard Ribalet, Filippo Mancia, Dean BokAbstract:Vitamin A has diverse biological functions and is essential for human survival at every point from embryogenesis to adulthood. Vitamin A and its derivatives have been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental, but how its transport is regulated is poorly understood. STRA6 is a multitransmembrane domain cell-surface receptor and mediates vitamin A uptake from plasma retinol binding protein (RBP). STRA6 can mediate both cellular vitamin A influx and efflux, but what regulates these opposing activities is unknown. To answer this question, we purified and identified STRA6-associated proteins in a native mammalian cell type that takes up vitamin A through STRA6 using mass spectrometry. We found that the major protein repeatedly identified as STRA6-associated protein is calmodulin, consistent with the cryogenic electron microscopy (cryo-EM) study of zebrafish STRA6 associated with calmodulin. Using radioactivity-based, high-performance liquid chromatography (HPLC)-based and real-time fluorescence techniques, we found that calmodulin profoundly affects STRA6's vitamin A transport activity. Increased calcium/calmodulin promotes cellular vitamin A efflux and suppresses vitamin A influx through STRA6. Further mechanistic studies revealed that calmodulin enhances the binding of apo-RBP to STRA6, and this enhancement is much more pronounced for apo-RBP than holo-RBP. This study revealed that calmodulin regulates STRA6's vitamin A influx or efflux activity by modulating its preferential interaction with apo-RBP or holo-RBP. This molecular mechanism of regulating vitamin A transport may point to new directions to treat human diseases associated with insufficient or excessive vitamin A uptake.
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How Free Retinol Behaves Differently from RBP-Bound Retinol in
2016Co-Authors: Rbp Receptor-mediated, Ming Zhong, Riki Kawaguchi, Miki Kassai, Vitamin A Uptake, Hui SunAbstract:Berry et al. claimed that holo-retinol-binding protein (holo-RBP) binds to STRA6 to trigger insulin resistance but does not contribute to retinol uptake from holo-RBP (1). These claims, based on improperly performed assays, contradict many studies on STRA6 (2–10) and the findings that apo-RBP, not holo-RBP, is elevated in cases of obesity and type 2 diabetes (11, 12). The claims of Berry et al. also contradict two independent studies published in Molecular and Cellular Biology showing that RBP’s role in insu-lin resistance is independent of STRA6 and retinol (13, 14). Properly formed retinol/RBP complex, a cell type that is con-firmed to express the STRA6 protein, and the ability to distinguish true intracellular uptake from nonspecific binding (e.g., nonspe-cific sticking of [3H]retinol or [3H]retinol/RBP to plastic or cell surfaces) are prerequisites in STRA6-dependent vitamin A uptake assays. It has been well established from numerous studies, includ-ing crystallographic studies, that retinol forms a 1:1 complex with RBP. However, Berry et al. performed all [3H]retinol uptake as-says by mixing free [3H]retinol with unlabeled holo-RBP and ap-plying this mixture without removing free [3H]retinol. Because [3H]retinol/RBP was not properly formed and no free [3H]retinol was removed, this assay is a free [3H]retinol diffusion assay, not an assay of STRA6-mediated [3H]retinol uptake from the [3H]reti-nol/RBP complex (Fig. 1). It has been known since the 1970s that retinyl ester bound to lipoproteins is an RBP-independent mechanism of delivering vi-tamin A (15). Since RBP knockout mice have primarily vision defects under vitamin A-sufficient conditions (16, 17), it is no
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Vitamin A transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein.
PloS one, 2013Co-Authors: Ming Zhong, Riki Kawaguchi, Mariam Ter-stepanian, Miki Kassai, Hui SunAbstract:Vitamin A and its derivatives (retinoids) play diverse and crucial functions from embryogenesis to adulthood and are used as therapeutic agents in human medicine for eye and skin diseases, infections and cancer. Plasma retinol binding protein (RBP) is the principal and specific vitamin A carrier in the blood and binds vitamin A at 1∶1 ratio. STRA6 is the high-affinity membrane receptor for RBP and mediates cellular vitamin A uptake. STRA6 null mice have severely depleted vitamin A reserves for vision and consequently have vision loss, even under vitamin A sufficient conditions. STRA6 null humans have a wide range of severe pathological phenotypes in many organs including the eye, brain, heart and lung. Known membrane transport mechanisms involve transmembrane pores that regulate the transport of the substrate (e.g., the gating of ion channels). STRA6 represents a new type of membrane receptor. How this receptor interacts with its transport substrate vitamin A and the functions of its nine transmembrane domains are still completely unknown. These questions are critical to understanding the molecular basis of STRA6′s activities and its regulation. We employ acute chemical modification to introduce chemical side chains to STRA6 in a site-specific manner. We found that modifications with specific chemicals at specific positions in or near the transmembrane domains of this receptor can almost completely suppress its vitamin A transport activity. These experiments provide the first evidence for the existence of a transmembrane pore, analogous to the pore of ion channels, for this new type of cell-surface receptor.
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Differential and Isomer-Specific Modulation of Vitamin A Transport and the Catalytic Activities of the RBP Receptor by Retinoids
The Journal of Membrane Biology, 2013Co-Authors: Riki Kawaguchi, Ming Zhong, Mariam Ter-stepanian, Miki Kassai, Hui SunAbstract:Retinoids are vitamin A derivatives with diverse biological functions. Both natural and artificial retinoids have been used as therapeutic reagents to treat human diseases, but not all retinoid actions are understood mechanistically. Plasma retinol binding protein (RBP) is the principal and specific carrier of vitamin A in the blood. STRA6 is the membrane receptor for RBP that mediates cellular vitamin A uptake. The effects of retinoids or related compounds on the receptor’s vitamin A uptake activity and its catalytic activities are not well understood. In this study, we dissected the membrane receptor-mediated vitamin A uptake mechanism using various retinoids. We show that a subset of retinoids strongly stimulates STRA6-mediated vitamin A release from holo-RBP. STRA6 also catalyzes the exchange of retinol in RBP with certain retinoids. The effect of retinoids on STRA6 is highly isomer-specific. This study provides unique insights into the RBP receptor’s mechanism and reveals that the vitamin A transport machinery can be a target of retinoid-based drugs.
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Effect of MTSEA-biotin modification on STRA6-mediated vitamin A uptake as measured by 3H-retinol uptake from 3H-retinol/RBP and HPLC analysis of retinyl esters.
2013Co-Authors: Ming Zhong, Riki Kawaguchi, Mariam Ter-stepanian, Miki Kassai, Hui SunAbstract:A. Positions of V320C and S385C in the transmembrane topology model of STRA6. Because MTSEA-biotin is membrane impermeable, the location of S385C close to the intracellular side of STRA6 makes it inaccessible to MTSEA-biotin from the extracellular side, while V320C is positioned on the boundary of membrane helix VI and extracellular domain and can be accessed by MTSEA-biotin from the extracellular side. B and C. Cell-free vitamin A uptake assays comparing the effect of MTSEA-biotin treatment on STRA6-WT (WT) and STRA6-S385C (S385C). B is 3H-retinol uptake assay from 3H-retinol/RBP. C is HPLC-based retinyl ester analysis of retinol uptake from holo-RBP. D and E. Live-cell vitamin A uptake assays comparing the effect of MTSEA-biotin treatment on STRA6-WT (WT) and STRA6-V320C (V320C). D is 3H-retinol uptake assay from 3H-retinol/RBP. E is HPLC-based retinyl ester analysis of retinol uptake from holo-RBP. In B and D, the amount of 3H-retinol associated with STRA6-WT without modification is defined as 100%. This activity reflects the binding of 3H-retinol/RBP to STRA6. In C and E, the activity of STRA6-WT with LRAT as measured by retinyl ester amount is defined as 100%. Grey bars, no treatment. Green bars, MTSEA-biotin treatment.
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Regulatory mechanism for the transmembrane receptor that mediates bidirectional vitamin A transport.
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Ming Zhong, Riki Kawaguchi, Miki Kassai, Brianna Costabile, Yuyan Tang, Guo Cheng, Bernard Ribalet, Filippo Mancia, Dean BokAbstract:Vitamin A has diverse biological functions and is essential for human survival at every point from embryogenesis to adulthood. Vitamin A and its derivatives have been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental, but how its transport is regulated is poorly understood. STRA6 is a multitransmembrane domain cell-surface receptor and mediates vitamin A uptake from plasma retinol binding protein (RBP). STRA6 can mediate both cellular vitamin A influx and efflux, but what regulates these opposing activities is unknown. To answer this question, we purified and identified STRA6-associated proteins in a native mammalian cell type that takes up vitamin A through STRA6 using mass spectrometry. We found that the major protein repeatedly identified as STRA6-associated protein is calmodulin, consistent with the cryogenic electron microscopy (cryo-EM) study of zebrafish STRA6 associated with calmodulin. Using radioactivity-based, high-performance liquid chromatography (HPLC)-based and real-time fluorescence techniques, we found that calmodulin profoundly affects STRA6's vitamin A transport activity. Increased calcium/calmodulin promotes cellular vitamin A efflux and suppresses vitamin A influx through STRA6. Further mechanistic studies revealed that calmodulin enhances the binding of apo-RBP to STRA6, and this enhancement is much more pronounced for apo-RBP than holo-RBP. This study revealed that calmodulin regulates STRA6's vitamin A influx or efflux activity by modulating its preferential interaction with apo-RBP or holo-RBP. This molecular mechanism of regulating vitamin A transport may point to new directions to treat human diseases associated with insufficient or excessive vitamin A uptake.
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How Free Retinol Behaves Differently from RBP-Bound Retinol in
2016Co-Authors: Rbp Receptor-mediated, Ming Zhong, Riki Kawaguchi, Miki Kassai, Vitamin A Uptake, Hui SunAbstract:Berry et al. claimed that holo-retinol-binding protein (holo-RBP) binds to STRA6 to trigger insulin resistance but does not contribute to retinol uptake from holo-RBP (1). These claims, based on improperly performed assays, contradict many studies on STRA6 (2–10) and the findings that apo-RBP, not holo-RBP, is elevated in cases of obesity and type 2 diabetes (11, 12). The claims of Berry et al. also contradict two independent studies published in Molecular and Cellular Biology showing that RBP’s role in insu-lin resistance is independent of STRA6 and retinol (13, 14). Properly formed retinol/RBP complex, a cell type that is con-firmed to express the STRA6 protein, and the ability to distinguish true intracellular uptake from nonspecific binding (e.g., nonspe-cific sticking of [3H]retinol or [3H]retinol/RBP to plastic or cell surfaces) are prerequisites in STRA6-dependent vitamin A uptake assays. It has been well established from numerous studies, includ-ing crystallographic studies, that retinol forms a 1:1 complex with RBP. However, Berry et al. performed all [3H]retinol uptake as-says by mixing free [3H]retinol with unlabeled holo-RBP and ap-plying this mixture without removing free [3H]retinol. Because [3H]retinol/RBP was not properly formed and no free [3H]retinol was removed, this assay is a free [3H]retinol diffusion assay, not an assay of STRA6-mediated [3H]retinol uptake from the [3H]reti-nol/RBP complex (Fig. 1). It has been known since the 1970s that retinyl ester bound to lipoproteins is an RBP-independent mechanism of delivering vi-tamin A (15). Since RBP knockout mice have primarily vision defects under vitamin A-sufficient conditions (16, 17), it is no
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To investigate the necessity of STRA6 upregulation in T cells during T cell immune responses.
PLoS ONE, 2013Co-Authors: Rafik Terra, Ming Zhong, Hui Sun, Xuehai Wang, Tania Charpentier, Alain Lamarre, Jianning Mao, Hongyu LuoAbstract:Our earlier study revealed that STRA6 (stimulated by retinoic acid gene 6) was up-regulated within 3 h of TCR stimulation. STRA6 is the high-affinity receptor for plasma retinol-binding protein (RBP) and mediates cellular vitamin A uptake. We generated STRA6 knockout (KO) mice to assess whether such up-regulation was critical for T-cell activation, differentiation and function. STRA6 KO mice under vitamin A sufficient conditions were fertile without apparent anomalies upon visual inspection. The size, cellularity and lymphocyte subpopulations of STRA6 KO thymus and spleen were comparable to those of their wild type (WT) controls. KO and WT T cells were similar in terms of TCR-stimulated proliferation in vitro and homeostatic expansion in vivo. Naive KO CD4 cells differentiated in vitro into Th1, Th2, Th17 as well as regulatory T cells in an analogous manner as their WT counterparts. In vivo experiments revealed that anti-viral immune responses to lymphocytic choriomeningitis virus in KO mice were comparable to those of WT controls. We also demonstrated that STRA6 KO and WT mice had similar glucose tolerance. Total vitamin A levels are dramatically lower in the eyes of KO mice as compared to those of WT mice, but the levels in other organs were not significantly affected after STRA6 deletion under vitamin A sufficient conditions, indicating that the eye is the mouse organ most sensitive to the loss of STRA6. Our results demonstrate that 1) in vitamin A sufficiency, the deletion of STRA6 in T cells does no affect the T-cell immune responses so-far tested, including those depend on STAT5 signaling; 2) STRA6-independent vitamin A uptake compensated the lack of STRA6 in lymphoid organs under vitamin A sufficient conditions in mice; 3) STRA6 is critical for vitamin A uptake in the eyes even in vitamin A sufficiency.
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Vitamin A transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein.
PloS one, 2013Co-Authors: Ming Zhong, Riki Kawaguchi, Mariam Ter-stepanian, Miki Kassai, Hui SunAbstract:Vitamin A and its derivatives (retinoids) play diverse and crucial functions from embryogenesis to adulthood and are used as therapeutic agents in human medicine for eye and skin diseases, infections and cancer. Plasma retinol binding protein (RBP) is the principal and specific vitamin A carrier in the blood and binds vitamin A at 1∶1 ratio. STRA6 is the high-affinity membrane receptor for RBP and mediates cellular vitamin A uptake. STRA6 null mice have severely depleted vitamin A reserves for vision and consequently have vision loss, even under vitamin A sufficient conditions. STRA6 null humans have a wide range of severe pathological phenotypes in many organs including the eye, brain, heart and lung. Known membrane transport mechanisms involve transmembrane pores that regulate the transport of the substrate (e.g., the gating of ion channels). STRA6 represents a new type of membrane receptor. How this receptor interacts with its transport substrate vitamin A and the functions of its nine transmembrane domains are still completely unknown. These questions are critical to understanding the molecular basis of STRA6′s activities and its regulation. We employ acute chemical modification to introduce chemical side chains to STRA6 in a site-specific manner. We found that modifications with specific chemicals at specific positions in or near the transmembrane domains of this receptor can almost completely suppress its vitamin A transport activity. These experiments provide the first evidence for the existence of a transmembrane pore, analogous to the pore of ion channels, for this new type of cell-surface receptor.
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Differential and Isomer-Specific Modulation of Vitamin A Transport and the Catalytic Activities of the RBP Receptor by Retinoids
The Journal of Membrane Biology, 2013Co-Authors: Riki Kawaguchi, Ming Zhong, Mariam Ter-stepanian, Miki Kassai, Hui SunAbstract:Retinoids are vitamin A derivatives with diverse biological functions. Both natural and artificial retinoids have been used as therapeutic reagents to treat human diseases, but not all retinoid actions are understood mechanistically. Plasma retinol binding protein (RBP) is the principal and specific carrier of vitamin A in the blood. STRA6 is the membrane receptor for RBP that mediates cellular vitamin A uptake. The effects of retinoids or related compounds on the receptor’s vitamin A uptake activity and its catalytic activities are not well understood. In this study, we dissected the membrane receptor-mediated vitamin A uptake mechanism using various retinoids. We show that a subset of retinoids strongly stimulates STRA6-mediated vitamin A release from holo-RBP. STRA6 also catalyzes the exchange of retinol in RBP with certain retinoids. The effect of retinoids on STRA6 is highly isomer-specific. This study provides unique insights into the RBP receptor’s mechanism and reveals that the vitamin A transport machinery can be a target of retinoid-based drugs.