A Membrane Receptor for Retinol Binding Protein Mediates Cellular Uptake of Vitamin A

Kawaguchi, Riki; Yu, Jiamei; Honda, Jane; Hu, Jane; Whitelegge, Julian P.; Ping, Peipei; Wiita, Patrick; Bok, Dean; Sun, Hui

doi:10.1126/science.1136244

Cited by 692 publications

(766 citation statements)

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“…It has been shown that Stra6 binds to holo-RBP and is necessary for the cellular uptake of retinol, therefore having an important upstream role in RA signalling. This was confirmed by the fact that Stra6 mutations observed in humans are responsible for familial syndromes likely to be related to the role of vitamin A in embryonic development, 21 which include severe malformations such as anophtalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary displasia, lung hypoplasia and mental retardation. 23 Consistent with this, a Stra6 knockout mouse model showed several ocular defects similar to those described in humans.…”

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confidence: 57%

“…20 Recently, it was discovered that Stra6 is the specific membrane receptor for RBP. 21 The existence of such a receptor was previously discovered in the 1970s, 22 but its identification remained elusive. It has been shown that Stra6 binds to holo-RBP and is necessary for the cellular uptake of retinol, therefore having an important upstream role in RA signalling.…”

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confidence: 99%

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Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

et al. 2013

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Stra6 is the retinoic acid (RA)-inducible gene encoding the cellular receptor for holo-retinol binding protein. This transmembrane protein mediates the internalization of retinol, which then upregulates RA-responsive genes in target cells. Here, we show that Stra6 can be upregulated by DNA damage in a p53-dependent manner, and it has an important role in cell death responses. Stra6 expression induced significant amounts of apoptosis in normal and cancer cells, and it was also able to influence p53-mediated cell fate decisions by turning an initial arrest response into cell death. Moreover, inhibition of Stra6 severely compromised p53-induced apoptosis. We also found that Stra6 induced mitochondria depolarization and accumulation of reactive oxygen species, and that it was present not only at the cellular membrane but also in the cytosol. Finally, we show that these novel functions of Stra6 did not require downstream activation of RA signalling. Our results present a previously unknown link between the RA and p53 pathways and provide a rationale to use retinoids to upregulate Stra6, and thus enhance the tumour suppressor functions of p53. This may have implications for the role of vitamin A metabolites in cancer prevention and treatment.

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confidence: 57%

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Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

et al. 2013

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“…RA exerts additional biological effects through dimerization of RXR with an array of other type II nuclear receptors (13). Various approaches have been used to determine effectors of retinoid metabolism, such as genetic alteration of retinoid-binding proteins (16)(17)(18)(19)(20)(21), enzymes (22)(23)(24)(25), and receptors (12,13,26), dietary manipulation of vitamin A intake (28), and exposure to xenobiotics (29)(30)(31)(32). Quantifying how manipulation of retinoid metabolism effects the flux of retinoids through metabolic paths and/or effects availability of substrate for RA production will provide insight into retinoid homeostasis and metabolism, and thereby function.…”

Section: Introductionmentioning

confidence: 99%

HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues

Kane

Folias

Napoli

2008

Analytical Biochemistry

154

160

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We report robust HPLC/UV methods for quantifying retinyl esters (RE), retinol (ROL) and retinal (RAL) applicable to diverse biological samples, with lower limits of detection of 0.7 pmol, 0.2 pmol, and 0.2 pmol, respectively, and linear ranges >3 orders of magnitude. These assays function well with small, complex biological samples (10-20 mg tissue). Coefficients of variation range from: intra-day, 5.9-10.0%; inter-day, 5.9-11.0%. Quantification of endogenous RE, ROL, and RAL in mouse serum and tissues (liver, kidney, adipose, muscle, spleen, testis, skin, brain, and brain regions) reveals utility. Ability to discriminate spatial concentrations of ROL and RE is illustrated with C57BL/6 mouse brain loci (hippocampus, cortex, olfactory bulb, thalamus, cerebellum, and striatum.) We also developed a method to distinguish isomeric forms of ROL to investigate precursors of retinoic acid. The ROL isomer assay has limits of detection between 3.5-4.5 pmol and a similar linear range and % CV as the ROL/RE and RAL assays. The assays described here provide for sensitive and rigorous quantification of endogenous RE, ROL, and RAL to elucidate retinoid homeostasis in disease states, such as Alzheimer's disease, type 2 diabetes, obesity, and cancer.

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“…Using an unbiased strategy, the membrane receptor for RBP has been identified as a multitransmembrane domain protein STRA6. STRA6 binds to RBP with high-affinity and mediates cellular uptake of vitamin A from the retinol/RBP complex (holo-RBP) (26). STRA6 represents a rare example of a eukaryotic membrane transport system that depends on an extracellular carrier protein but does not rely on endocytosis.…”

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Mapping the Membrane Topology and Extracellular Ligand Binding Domains of the Retinol Binding Protein Receptor

Kawaguchi¹,

Yu²,

Wiita³

et al. 2008

Biochemistry

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STRA6 is a multi-transmembrane domain protein not homologous to any other proteins with known function. It functions as the high-affinity receptor for plasma retinol binding protein (RBP) and mediates cellular vitamin A uptake from the vitamin A/RBP complex. Consistent with the diverse roles of vitamin A and the wide tissue expression pattern of STRA6, mutations in STRA6 are associated with severe pathological phenotypes in human. The structural basis for STRA6's biochemical function is unknown. Although computer programs predict 11 transmembrane domains for STRA6, its topology has never been studied experimentally. Elucidating the transmembrane topology of STRA6 is critical for understanding its structure and function. By inserting an epitope tag into all possible extracellular and intracellular domains of STRA6, we systematically analyzed the accessibility of each tag on the surface of live cells, the accessibility of each tag in permeabilized cells, the effect of each tag on RBP binding and STRA6-mediated vitamin A uptake from the vitamin A/RBP complex. In addition, we used a new lysine accessibility technique combining cell-surface biotinylation and tandem-affinity purification to study a region of the protein not revealed by the epitope-tagging method. These studies not only revealed STRA6's extracellular, transmembrane and intracellular domains, but also implicated extracellular regions of STRA6 in RBP binding.Vitamin A and its derivatives (retinoids) are essential for diverse aspects of vertebrate physiology (1-3). Due to the hydrophobic nature of retinoids, it has been assumed that random diffusion is the primary if not the only means of transmembrane transport. However, biochemical evidence suggests that retinol uptake from the small intestine is mediated by a membrane transporter (4). There is also strong evidence for the existence of a specific mechanism to transport 11-cis retinal in the retinal pigment epithelium (RPE) that depends on interphotoreceptor retinoid-binding protein (IRBP). Apo-IRBP is much more effective in promoting the release of 11-cis retinal from the RPE than the apo-forms of other retinoid binding proteins (5). In addition, apo-IRBP is only effective when it is present on the apical, but not basal, side of the RPE (6). Another finding that challenges the assumptions about random diffusion is the identification of an ATP-dependent transporter (ABCR or ABCA4) that transports all-trans retinal released from bleached rhodopsin across membranes (7-9). Mutations in ABCR cause a wide spectrum of human vision diseases from retinitis pigmentosa to macular degeneration. Prior to the surprising discovery of ABCR's role in † This project was supported by National Institute of Health grant 1R01EY018144 (H.S.).

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A Membrane Receptor for Retinol Binding Protein Mediates Cellular Uptake of Vitamin A

Cited by 692 publications

References 31 publications

Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues

Mapping the Membrane Topology and Extracellular Ligand Binding Domains of the Retinol Binding Protein Receptor

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