Vitamin A receptor

Last updated
Vitamin A receptor
Identifiers
Symbol?
InterPro IPR026612
TCDB 2.A.90
OPM superfamily 448
OPM protein 5sy1
stimulated by retinoic acid gene 6 homolog (mouse)
Identifiers
SymbolSTRA6
NCBI gene 64220
HGNC 30650
OMIM 610745
PDB 5sy1
RefSeq NM_022369
UniProt Q7Z3U9
Other data
Locus Chr. 15 q24.1
Search for
Structures Swiss-model
Domains InterPro

Vitamin A receptor, Stimulated by retinoic acid 6 or STRA6 protein was originally discovered as a transmembrane cell-surface receptor for retinol-binding protein. [1] [2] [3] STRA6 is unique as it functions both as a membrane transporter and a cell surface receptor, particularly as a cytokine receptor. In fact, STRA6 may be the first of a whole new class of proteins that might be known as "cytokine signaling transporters." [4] STRA6 is primarily known as the receptor for retinol binding protein and for its relevance in the transport of retinol to specific sites such as the eye (Vitamin A). [5] It does this through the removal of retinol (ROH) from the holo-Retinol Binding Protein (RBP) and transports it into the cell to be metabolized into retinoids and/or kept as a retinylester. [6] As a receptor, after holo-RBP is bound, STRA6 activates the JAK/STAT pathway, resulting in the activation of transcription factor, STAT5. These two functions—retinol transporter and cytokine receptor—while using different pathways, are processes that depend on each other. [7]

Contents

Mechanism of action

Overview

In the first step, holo-retinol binding protein (holo-RBP; simply means RBP bound to retinol, i.e. the RBP-ROH complex) binds to the extracellular portion of STRA6. This facilitates the release of retinol through the transporter. ROH is then transferred to cellular retinol binding protein 1 (CRBP1), an intracellular acceptor of retinol that attaches to the CRBP Binding Loop (or CBL) on STRA6. This transport of ROH, in turn, activates JAK2, thereby phosphorylating STRA6 at the Y643 (tyrosine) residue. [7] This phosphorylation enables the extension of the CBL further into the cell. Holo-CRBP-I, leaves the CBL and is replaced by apo-CRBP-I (unbound). Holo-CRBP-I will continue to the Endoplasmic Reticulum (ER) where lecithin retinol acyltransferase (LRAT) is bound. ROH is released to LRAT which will convert retinol into retinylesters. [6] Following the release of holo-CRBP-I from intercellular STRA6, STAT5 is recruited to STRA6 phosphorylated Y643 region where it is then phosphorylated by JAK2. This phosphorylation activates STAT5 which then makes its way to the nucleus to induce expression of target genes including suppressor of cytokine signaling 3 (SOCS3), a strong inhibitor of insulin signaling. [6]

Interdependency of cytokine signaling transporter functions

Research has demonstrated that overexpression of CRBP-I increases the ability of RBP-ROH complex to phosphorylate STRA6 and, later, JAK2 and STAT5. Suppressing CRBP-I, on the other hand, led to decreased ability of RBP-ROH complex to phosphorylate STRA6 and signaling components. Similarly, reducing the expression of LRAT also decreased the ability of RBP-ROH complex to phosphorylate JAK2 and STAT5. [7] Therefore, both CRBP-I and LRAT are necessary for the STRA6 signaling cascade upon the binding and transport of retinol. JAK2 is also conversely responsible for the activation of STRA6, after which apo-CRBP-I is recruited to the intercellular CBL of STRA6 and vitamin A might be transferred by the receptor to CRBP-I. [7] Thus, both STRA6 signaling and STRA6 transport of vitamin A are dependent upon each other. Uptake of retinol is required for STRA6 signaling and JAK2 activation of STRA6 is necessary for retinol uptake.

Clinical significance

STRA6 can be found at high levels in various tissues including: the choroid plexus, the brain microvascular, tesis, the spleen, kidney, eye, the placenta, and the female reproductive tract. However, it is surprisingly not found in liver tissue where Vitamin A (retinol) is primarily stored. [8] [9] Because of its importance in Vitamin A transport, STRA6 mutations are more commonly associated with problems with eye such as a reduction in retinal thickness and shortening of the inner and outer segments of rod photoreceptors. Therefore, as might be expected, STRA6 mutations result in a number of different abnormalities of the eye such as Microphthalmia, Anophthalmia, and Coloboma. [9] [10]

However, STRA6 is clearly vital for more than just eye development as it is expressed in many different tissues detailed above. Other disorders that result from STRA6 mutations include pulmonary dysgenesis, cardiac malformations, and mental retardation. In fact, research has shown that homozygous mutations in human STRA6 gene can lead to Matthew-Wood syndrome, which is a combination of all the mentioned disorders. In this respect, STRA6 mutations can be particularly fatal during the embryonic stage. [8] [9]

STRA6 has also been associated with facilitating insulin resistance. This is because STRA6 signaling results in activation of transcription factor STAT5 target genes. One of these target genes is a suppressor of cytokine signaling 3 (SOCS3) which is a strong inhibitor of insulin signaling. As a result, STRA6 signaling suppresses the response to insulin by inhibiting the phosphorylation of the insulin receptor, IR, by an influx of insulin. [7] In other words, increased levels of the RBP in obese animals (which will increase STRA6 activity) can facilitate insulin resistance. Due to this close relationship between STRA6 and insulin resistance, it has been demonstrated that single nucleotide polymorphisms in STRA6 are associated with Type 2 Diabetes. [7]

Related Research Articles

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Insulin receptor</span> Mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

<span class="mw-page-title-main">Oncostatin M</span> Mammalian protein found in Homo sapiens

Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.

<span class="mw-page-title-main">GRB2</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.

<span class="mw-page-title-main">PTPN11</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.

<span class="mw-page-title-main">Interferon-gamma receptor</span> Mammalian protein found in Homo sapiens

The interferon-gamma receptor (IFNGR) protein complex is the heterodimer of two chains: IFNGR1 and IFNGR2. It binds interferon-γ, the sole member of interferon type II.

<span class="mw-page-title-main">Retinol binding protein 4</span> Protein-coding gene in the species Homo sapiens

Retinol binding protein 4, also known as RBP4, is a transporter protein for retinol. RBP4 has a molecular weight of approximately 21 kDa and is encoded by the RBP4 gene in humans. It is mainly, though not exclusively, synthesized in the liver and circulates in the bloodstream as a hepatokine bound to retinol in a complex with transthyretin. RBP4 has been a drug target for ophthalmology research due to its role in vision. RBP4 may also be involved in metabolic diseases as suggested by recent studies.

<span class="mw-page-title-main">STAT5</span> Protein family

Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level. STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes. Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers, and silencing this aberrant activity is an area of active research in medicinal chemistry.

<span class="mw-page-title-main">Tyrosine kinase 2</span> Enzyme and coding gene in humans

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.

<span class="mw-page-title-main">Janus kinase 1</span>

JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family, the IL-4 receptor family, the gp130 receptor family. It is also important for transducing a signal by type I (IFN-α/β) and type II (IFN-γ) interferons, and members of the IL-10 family via type II cytokine receptors. Jak1 plays a critical role in initiating responses to multiple major cytokine receptor families. Loss of Jak1 is lethal in neonatal mice, possibly due to difficulties suckling. Expression of JAK1 in cancer cells enables individual cells to contract, potentially allowing them to escape their tumor and metastasize to other parts of the body.

The visual cycle is a process in the retina that replenishes the molecule retinal for its use in vision. Retinal is the chromophore of most visual opsins, meaning it captures the photons to begin the phototransduction cascade. When the photon is absorbed, the 11-cis retinal photoisomerizes into all-trans retinal as it is ejected from the opsin protein. Each molecule of retinal must travel from the photoreceptor cell to the RPE and back in order to be refreshed and combined with another opsin. This closed enzymatic pathway of 11-cis retinal is sometimes called Wald's visual cycle after George Wald (1906–1997), who received the Nobel Prize in 1967 for his work towards its discovery.

<span class="mw-page-title-main">SOCS3</span> Protein

Suppressor of cytokine signaling 3 is a protein that in humans is encoded by the SOCS3 gene. This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling.

<span class="mw-page-title-main">Suppressor of cytokine signaling 1</span> Protein-coding gene in the species Homo sapiens

Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the SOCS1 gene. SOCS1 orthologs have been identified in several mammals for which complete genome data are available.

<span class="mw-page-title-main">Thrombopoietin receptor</span> Protein-coding gene in the species Homo sapiens

The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 is a protein that in humans is encoded by the MPL oncogene.

<span class="mw-page-title-main">RBP1</span> Protein-coding gene in the species Homo sapiens

Retinol binding protein 1, cellular, also known as RBP1, is a protein that in humans is encoded by the RBP1 gene.

Interleukin 20 receptors (IL20R) belong to the IL-10 family. IL20R are involved in both pro-inflammatory and anti-inflammatory immune response. There are two types of IL20R: Type I and Type II.

A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

<span class="mw-page-title-main">Retinol-binding protein</span> Family of proteins that bind retinol

Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies.

References

  1. ↑ Blaner WS (March 2007). "STRA6, a cell-surface receptor for retinol-binding protein: the plot thickens". Cell Metabolism. 5 (3): 164–6. doi: 10.1016/j.cmet.2007.02.006 . PMID   17339024.
  2. ↑ Berry DC, O'Byrne SM, Vreeland AC, Blaner WS, Noy N (August 2012). "Cross talk between signaling and vitamin A transport by the retinol-binding protein receptor STRA6". Molecular and Cellular Biology. 32 (15): 3164–75. doi:10.1128/MCB.00505-12. PMC   3434520 . PMID   22665496.
  3. ↑ Ruiz A, Mark M, Jacobs H, Klopfenstein M, Hu J, Lloyd M, Habib S, Tosha C, Radu RA, Ghyselinck NB, Nusinowitz S, Bok D (May 2012). "Retinoid content, visual responses, and ocular morphology are compromised in the retinas of mice lacking the retinol-binding protein receptor, STRA6". Investigative Ophthalmology & Visual Science. 53 (6): 3027–39. doi:10.1167/iovs.11-8476. PMC   3378086 . PMID   22467576.
  4. ↑ Berry DC, O'Byrne SM, Vreeland AC, Blaner WS, Noy N (August 2012). "Cross talk between signaling and vitamin A transport by the retinol-binding protein receptor STRA6". Molecular and Cellular Biology. 32 (15): 3164–75. doi:10.1128/MCB.00505-12. PMC   3434520 . PMID   22665496.
  5. ↑ Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H (February 2007). "A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A". Science. 315 (5813): 820–5. Bibcode:2007Sci...315..820K. doi: 10.1126/science.1136244 . PMID   17255476. S2CID   25258551.
  6. 1 2 3 Berry DC, O'Byrne SM, Vreeland AC, Blaner WS, Noy N (August 2012). "Cross talk between signaling and vitamin A transport by the retinol-binding protein receptor STRA6". Molecular and Cellular Biology. 32 (15): 3164–75. doi:10.1128/MCB.00505-12. PMC   3434520 . PMID   22665496.
  7. 1 2 3 4 5 6 Berry DC, O'Byrne SM, Vreeland AC, Blaner WS, Noy N (August 2012). "Cross talk between signaling and vitamin A transport by the retinol-binding protein receptor STRA6". Molecular and Cellular Biology. 32 (15): 3164–75. doi:10.1128/MCB.00505-12. PMC   3434520 . PMID   22665496.
  8. 1 2 Blaner WS (March 2007). "STRA6, a cell-surface receptor for retinol-binding protein: the plot thickens". Cell Metabolism. 5 (3): 164–6. doi: 10.1016/j.cmet.2007.02.006 . PMID   17339024.
  9. 1 2 3 Ruiz A, Mark M, Jacobs H, Klopfenstein M, Hu J, Lloyd M, Habib S, Tosha C, Radu RA, Ghyselinck NB, Nusinowitz S, Bok D (May 2012). "Retinoid content, visual responses, and ocular morphology are compromised in the retinas of mice lacking the retinol-binding protein receptor, STRA6". Investigative Ophthalmology & Visual Science. 53 (6): 3027–39. doi:10.1167/iovs.11-8476. PMC   3378086 . PMID   22467576.
  10. ↑ Casey J, Kawaguchi R, Morrissey M, Sun H, McGettigan P, Nielsen JE, Conroy J, Regan R, Kenny E, Cormican P, Morris DW, Tormey P, Chróinín MN, Kennedy BN, Lynch S, Green A, Ennis S (December 2011). "First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: a new dimension to the STRA6 phenotype". Human Mutation. 32 (12): 1417–26. doi:10.1002/humu.21590. PMC   3918001 . PMID   21901792.
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