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 [6] and/or kept as a retinylester. [7] 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. [8]

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. [8] 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. [7] 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. [7]

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. [8] 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. [8] 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. [9] [10] 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. [10] [11]

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. [9] [10]

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. [8] 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. [8]

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Enzyme

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.

A hormone receptor is a receptor molecule that binds to a specific hormone. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptors for various ligands, such as fatty acids and prostaglandins. Hormone receptors are of mainly two classes. Receptors for peptide hormones tend to be cell surface receptors built into the plasma membrane of cells and are thus referred to as trans membrane receptors. An example of this is Actrapid. Receptors for steroid hormones are usually found within the protoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

<span class="mw-page-title-main">Insulin receptor</span> Cell receptor found in humans

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">Retinoid</span> Group of tetraterpenes

The retinoids are a class of chemical compounds that are natural derivatives of vitamin A or are chemically related to it. Synthetic retinoids are used in medicine where they regulate skin health, immunity and bone disorders.

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

The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the EPOR gene. EpoR is a 52 kDa peptide with a single carbohydrate chain resulting in an approximately 56–57 kDa protein found on the surface of EPO responding cells. It is a member of the cytokine receptor family. EpoR pre-exists as dimers. These dimers were originally thought to be formed by extracellular domain interactions, however, it is now assumed that it is formed by interactions of the transmembrane domain and that the original structure of the extracellular interaction site was due to crystallisation conditions and does not depict the native conformation. Binding of a 30 kDa ligand erythropoietin (Epo), changes the receptor's conformational change, resulting in the autophosphorylation of Jak2 kinases that are pre-associated with the receptor. At present, the best-established function of EpoR is to promote proliferation and rescue of erythroid progenitors from apoptosis.

<span class="mw-page-title-main">Interleukin 31</span>

Interleukin-31 (IL-31) is a protein that in humans is encoded by the IL31 gene that resides on chromosome 12. IL-31 is an inflammatory cytokine that helps trigger cell-mediated immunity against pathogens. It has also been identified as a major player in a number of chronic inflammatory diseases, including atopic dermatitis.

<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 found in humans

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">Janus kinase 2</span> Non-receptor tyrosine kinase and coding gene in humans

Janus kinase 2 is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family, the GM-CSF receptor family, the gp130 receptor family, and the single chain receptors.

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">STAT5A</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the STAT5A gene. STAT5A orthologs have been identified in several placentals for which complete genome data are available.

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

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<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.

<span class="mw-page-title-main">STAT5B</span> Protein-coding gene in the species Homo sapiens

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<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. ↑ Dhokia, Vinesh; Macip, Salvador (2024), Tappia, Paramjit S.; Shah, Anureet K.; Dhalla, Naranjan S. (eds.), "Retinoids and the Vitamin a Receptor STRA6 in Health and Disease", Lipophilic Vitamins in Health and Disease, Cham: Springer International Publishing, pp. 261–274, doi:10.1007/978-3-031-55489-6_13, ISBN   978-3-031-55489-6 , retrieved 2024-05-17
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. ↑ 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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