Cross Talk between Signaling and Vitamin A Transport by the Retinol-Binding Protein Receptor STRA6

Daniel C. Berry,^a,b Sheila M. O'Byrne,^c Amanda C. Vreeland,^b William S. Blaner,^c, and Noa Noy^a,b

Departments of Pharmacology,^a Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA,^b Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA,^c

Abstract: The plasma membrane protein STRA6 transports vitamin A from its blood carrier retinol binding protein (RBP) into cells, and it also functions as a cytokine receptor which activates JAK/STAT signaling. We show here that, unlike other cytokine receptors, phosphorylation of STRA6 is not simply induced upon binding of its extracellular ligand. Instead, activation of the receptor is triggered by STRA6-mediated translocation of retinol from serum RBP to an intracellular acceptor, the retinol-binding protein CRBP-I. The observations also demonstrate that the movement of retinol from RBP to CRBP-I, and thus activation of STRA6, is critically linked to the intracellular metabolism of the vitamin. Furthermore, the data show that STRA6 phosphorylation is required for retinol uptake to proceed. Hence, the observations demonstrate that STRA6 orchestrates a multicomponent "machinery" that couples vitamin A homeostasis and metabolism to activation of a signaling cascade and that, in turn, STRA6 signaling regulates the cellular uptake of the vitamin. STRA6 appears to be a founding member of a new class of proteins that may be termed "cytokine signaling transporters."

Address correspondence to Noa Noy, noa.noy{at}case.edu.

Supplemental material for this article may be found at http://mcb.asm.org/.

Transthyretin Blocks Retinol Uptake and Cell Signaling by the Holo-Retinol-Binding Protein Receptor STRA6.

D. C. Berry, C. M. Croniger, N. B. Ghyselinck, and N. Noy (2012)
Mol. Cell. Biol. 32, 3851-3859
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