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Science 315 (5813): 820-825

Copyright © 2007 by the American Association for the Advancement of Science

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

Riki Kawaguchi,1,2 Jiamei Yu,1 Jane Honda,1 Jane Hu,2 Julian Whitelegge,3,4 Peipei Ping,1,5 Patrick Wiita,1 Dean Bok,2,4,6 Hui Sun1,2,4*

Abstract: Vitamin A has diverse biological functions. It is transported in the blood as a complex with retinol binding protein (RBP), but the molecular mechanism by which vitamin A is absorbed by cells from the vitamin A–RBP complex is not clearly understood. We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A–RBP complex. It is widely expressed in embryonic development and in adult organ systems. The RBP receptor represents a major physiological mediator of cellular vitamin A uptake.

1 Department of Physiology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
2 Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, 100 Stein Plaza, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
3 Pasarow Mass Spectrometry Laboratory, Semel Institute, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
4 Brain Research Institute, UCLA, Los Angeles, CA 90095, USA.
5 Department of Medicine, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
6 Department of Neurobiology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA.

Note added in proof: A recent human genetic study (41) found that mutations in the human STRA6 gene are associated with widespread birth defects in multiple organ systems. This is consistent with the expression of STRA6 and the diverse functions of vitamin A in embryonic development.

* To whom correspondence should be addressed. E-mail: hsun{at}mednet.ucla.edu


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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E Van Aken, E A De Letter, M Veckeneer, L Derycke, T van Enschot, I Geers, S Delanghe, and J R Delanghe (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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K. Van Beneden, L. A. van Grunsven, C. Geers, M. Pauwels, A. Desmouliere, D. Verbeelen, A. Geerts, and C. Van den Branden (2008)
Nephrol. Dial. Transplant. 23, 3464-3471
   Abstract »    Full Text »    PDF »
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B. L. L. Maciel, H. G. Lacerda, J. W. Queiroz, J. Galvao, N. N. Pontes, R. Dimenstein, S. E. McGowan, L. F. C. Pedrosa, and S. M. B. Jeronimo (2008)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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C. Redondo, M. Vouropoulou, J. Evans, and J. B. C. Findlay (2008)
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   Abstract »    Full Text »    PDF »
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Q. Zhou, Y. Li, R. Nie, P. Friel, D. Mitchell, R. M. Evanoff, D. Pouchnik, B. Banasik, J. R. McCarrey, C. Small, et al. (2008)
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   Abstract »    Full Text »    PDF »
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Y.-K. Kim, L. Wassef, L. Hamberger, R. Piantedosi, K. Palczewski, W. S. Blaner, and L. Quadro (2008)
J. Biol. Chem. 283, 5611-5621
   Abstract »    Full Text »    PDF »
All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RAR{alpha}.
N. Chen and J. L. Napoli (2008)
FASEB J 22, 236-245
   Abstract »    Full Text »    PDF »
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A. Ruiz, N. B. Ghyselinck, N. Mata, S. Nusinowitz, M. Lloyd, C. Dennefeld, P. Chambon, and D. Bok (2007)
Invest. Ophthalmol. Vis. Sci. 48, 5377-5387
   Abstract »    Full Text »    PDF »
Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen.
B. R. Noble, R. P. Babiuk, R. D. Clugston, T. M. Underhill, H. Sun, R. Kawaguchi, P. G. Walfish, R. Blomhoff, T. E. Gundersen, and J. J. Greer (2007)
Am J Physiol Lung Cell Mol Physiol 293, L1079-L1087
   Abstract »    Full Text »    PDF »
Circulating Retinol-Binding Protein-4, Insulin Sensitivity, Insulin Secretion, and Insulin Disposition Index in Obese and Nonobese Subjects: Response to Stefan et al..
J.-M. Fernandez-Real, J. Vendrell, W. Ricart, C. Richart, and M. Broch (2007)
Diabetes Care 30, e92
   Full Text »    PDF »
CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells.
P. Ocaya, A. C. Gidlof, P. S. Olofsson, H. Torma, and A. Sirsjo (2007)
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   Abstract »    Full Text »    PDF »
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R. F. Burk, K. E. Hill, G. E. Olson, E. J. Weeber, A. K. Motley, V. P. Winfrey, and L. M. Austin (2007)
J. Neurosci. 27, 6207-6211
   Abstract »    Full Text »    PDF »

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