{"gene":"STRA6","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2007,"finding":"STRA6 was identified as a novel multi-transmembrane integral membrane protein. Structural analysis of missense mutations (P90L, P293L, T321P) suggested significant effects on the geometry of loops connecting transmembrane helices. Two C-terminal variations (T644M and R655C) alter an SH2-binding motif and a phosphorylation site, respectively, indicating these are functional sites.","method":"Homozygosity mapping, mutational analysis, structural modeling of transmembrane topology","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — structural modeling plus loss-of-function (protein absent in patient fibroblasts), single lab, multiple mutations analyzed but no in vitro reconstitution","pmids":["17273977"],"is_preprint":false},{"year":1997,"finding":"STRA6 encodes a highly hydrophobic membrane protein of a new type with no similarity to previously characterized integral membrane proteins. It is strongly expressed at blood-organ barriers (e.g., blood-testis barrier in Sertoli cells) with a spermatogenic cycle-dependent expression that is lost in RAR-alpha null mutants, suggesting it is a component of a retinoid transport machinery.","method":"Subtractive hybridization cDNA cloning, in situ hybridization, analysis of RAR-alpha null mutants","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — original identification by expression cloning and genetic model (RAR-alpha null), multiple tissues examined, single lab","pmids":["9203140"],"is_preprint":false},{"year":2008,"finding":"STRA6-dependent transfer of retinol from RBP4 into NIH 3T3 fibroblasts was enhanced by lecithin:retinol acyltransferase (LRAT). Retinol transfer was shown to be bidirectional, establishing that STRA6 acts as a retinol channel/transporter. Loss-of-function in zebrafish revealed that Stra6 deficiency caused vitamin A deprivation of developing eyes. In the absence of Stra6, holo-Rbp4 provoked non-specific vitamin A excess in embryonic tissues, impairing retinoic acid receptor signaling.","method":"Cell-based retinol transfer assay with LRAT co-expression, zebrafish morpholino knockdown, pharmacological and morpholino RBP4 reduction","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-based transport assay plus genetic loss-of-function in zebrafish with multiple phenotypic readouts, replicated across in vitro and in vivo systems","pmids":["18316031"],"is_preprint":false},{"year":2012,"finding":"STRA6 functions as both a retinol transporter and a cytokine receptor. Activation of STRA6 signaling (JAK/STAT cascade) is triggered not simply by holo-RBP binding but by STRA6-mediated translocation of retinol from serum RBP to the intracellular acceptor CRBP-I. STRA6 phosphorylation is required for retinol uptake to proceed, demonstrating that signaling and transport are critically interdependent.","method":"Phosphorylation assays, CRBP-I interaction studies, retinol uptake assays with phosphorylation-deficient STRA6 mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of phosphorylation sites, retinol transport assay, JAK/STAT signaling readout, multiple orthogonal methods in single lab","pmids":["22665496"],"is_preprint":false},{"year":2012,"finding":"Transthyretin (TTR) blocks the ability of holo-RBP to associate with STRA6, thereby suppressing both STRA6-mediated retinol uptake and STRA6-initiated JAK/STAT cell signaling. TTR protects mice from RBP-induced insulin resistance. STRA6 functions only when plasma RBP levels exceed TTR levels.","method":"Cell-based retinol uptake assay, JAK/STAT signaling assays, glucose tolerance tests in mice with TTR manipulation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical binding competition assay, in vivo insulin resistance model, multiple readouts in single lab","pmids":["22826435"],"is_preprint":false},{"year":2012,"finding":"STRA6 catalyzes bidirectional retinol transport: (1) influx — retinol release from holo-RBP coupled to CRBP-I or LRAT; (2) efflux — loading of free retinol into apo-RBP, driven by CRBP-I. Holo-RBP blocks STRA6-mediated efflux by competing with apo-RBP binding. STRA6 also catalyzes efficient retinol exchange between intracellular CRBP-I and extracellular RBP.","method":"In vitro retinol transport assays with purified components, competition binding assays","journal":"The Journal of membrane biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted transport assay demonstrating multiple catalytic activities, single lab with multiple orthogonal transport readouts","pmids":["22815070"],"is_preprint":false},{"year":2013,"finding":"Lecithin:retinol acyl transferase (LRAT), which esterifies retinol to retinyl esters, is necessary for activation of the STRA6/JAK2/STAT5 signaling cascade by holo-RBP. LRAT-null mice are protected from holo-RBP-induced suppression of insulin responses, establishing that STRA6 signaling requires retinol esterification to drive inward transport.","method":"LRAT-null mouse model, JAK2/STAT5 phosphorylation assays, insulin response measurements","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic null mouse model plus biochemical signaling assays, two orthogonal methods in single lab","pmids":["24036882"],"is_preprint":false},{"year":2013,"finding":"STRA6 functions as a cytokine receptor activating JAK2 and the transcription factors STAT3 and STAT5 upon holo-RBP binding. This signaling promotes oncogenic transformation and is critical for tumor formation by colon carcinoma cells in vivo.","method":"JAK2/STAT3/STAT5 phosphorylation assays, oncogenic transformation assay in fibroblasts, xenograft mouse model with STRA6 knockdown","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro signaling assays and in vivo xenograft model, single lab with two orthogonal methods","pmids":["25237067"],"is_preprint":false},{"year":2013,"finding":"STRA6 mediates bidirectional retinol transport in adipocyte precursors: holo-RBP4 triggers retinol influx and blocks adipocyte differentiation by activating RARα, while apo-RBP4 triggers retinol efflux, reducing cellular retinoids and RARα activity, thereby enhancing adipogenesis. Ectopic STRA6 synergized with apo-RBP4 to enhance adipogenesis.","method":"Cell-based retinol efflux/influx assays, RARα reporter assays, adipocyte differentiation assays, mouse liver RBP4 mobilization experiment","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — bidirectional transport reconstituted in cell culture, RARα activity measured, adipocyte differentiation readout, in vivo validation, single lab with multiple orthogonal methods","pmids":["23959802"],"is_preprint":false},{"year":2013,"finding":"STRA6 is essential for RBP-induced suppression of insulin signaling in vivo; Stra6-null mice are protected from RBP-induced insulin resistance. However, with the exception of the eye, ablation of Stra6 had only a modest effect on retinoid homeostasis in other tissues, demonstrating that STRA6's primary systemic function (outside the eye) is coupling circulating holo-RBP to JAK/STAT cell signaling rather than retinol delivery.","method":"Stra6-null mouse model, retinoid quantification by HPLC, insulin signaling assays, glucose tolerance tests","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mouse with multiple phenotypic readouts (retinoid homeostasis, insulin signaling, glucose tolerance), replicated across tissues, single lab","pmids":["23839944"],"is_preprint":false},{"year":2013,"finding":"Stra6 can be upregulated by DNA damage in a p53-dependent manner and plays a role in p53-induced apoptosis. Stra6 expression induced mitochondrial depolarization and accumulation of reactive oxygen species; inhibition of Stra6 compromised p53-induced apoptosis. These functions did not require downstream activation of retinoic acid signaling.","method":"DNA damage assays, p53-dependent transcriptional analysis, apoptosis assays, ROS measurement, mitochondrial membrane potential assay, Stra6 knockdown","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined apoptotic phenotype, multiple mechanistic readouts, single lab","pmids":["23449393"],"is_preprint":false},{"year":2014,"finding":"STRA6 is a bona fide vitamin A transporter critical for ocular vitamin A uptake. Stra6-knockout mice show markedly reduced ocular retinoids, malformations in the choroid and RPE, early cone photoreceptor cell death, and reduced rod outer segment length. STRA6-mediated uptake in the eye is a regulated process mandatory when RBP4 is the only transport mode. Vitamin A transport through the blood-CSF barrier in the choroid plexus was also impaired.","method":"Stra6-knockout mouse model, HPLC retinoid quantification, ophthalmic imaging, histology, electroretinography, pharmacological vitamin A rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal readouts (biochemical, histological, physiological, pharmacological rescue), replicated in multiple tissues","pmids":["24852372"],"is_preprint":false},{"year":2014,"finding":"The STRA6 G304K mutant protein is mislocalized and has severely reduced vitamin A uptake activity, establishing that membrane localization is required for STRA6 function. Inhibiting retinoic acid synthesis in zebrafish reproduced the colobomatous microanophthalmia phenotype, confirming diminished RA levels underlie the eye malformations.","method":"STRA6 G304K mutant expression and localization analysis, retinol uptake assay, zebrafish RA synthesis inhibition model","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional uptake assay plus localization study plus zebrafish disease model, single lab","pmids":["21901792"],"is_preprint":false},{"year":2016,"finding":"Cryo-EM structure of zebrafish STRA6 determined at 3.9 Å resolution revealed: (1) STRA6 has one intramembrane and nine transmembrane helices in a homodimeric assembly; (2) calmodulin is tightly bound to STRA6 in a noncanonical arrangement; (3) residues involved in RBP binding map to an arch-like structure covering a deep lipophilic cleft; (4) the cleft is open to the membrane, suggesting retinol internalization via direct diffusion into the lipid bilayer.","method":"Single-particle cryo-electron microscopy at 3.9 Å resolution","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structure determination by cryo-EM with functional mapping, foundational structural study providing mechanistic insight into transport and binding","pmids":["27563101"],"is_preprint":false},{"year":2016,"finding":"STRA6 is critical for vitamin A transport across blood-tissue barriers in the eyes, brain, and testis. In Stra6-knockout mice under vitamin A-deficient conditions, retinoid homeostasis in the eye, brain, and testis (but not in fat or lung) was severely impaired. Stra6 expression in testis and brain was regulated by vitamin A supply, reducing consumption when dietary supply was limited.","method":"Stra6-knockout mouse model with controlled dietary vitamin A, retinoid quantification in multiple tissues, retinoid-dependent physiological assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with dietary manipulation and multi-tissue biochemical analysis, multiple orthogonal readouts","pmids":["27189978"],"is_preprint":false},{"year":2017,"finding":"STRA6 mediates the inhibitory effect of RBP4 on insulin synthesis in pancreatic β-cells through the JAK2/STAT1/ISL-1 signaling pathway. STRA6 is expressed in β-cells and its activation by RBP4 suppresses glucose-stimulated insulin secretion.","method":"Primary islet isolation, INS-1E cell culture, RBP4 transgenic mouse model, JAK2/STAT1/ISL-1 pathway analysis, siRNA knockdown of STRA6","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model plus cell-based STRA6 knockdown with defined signaling pathway readout, single lab","pmids":["33199363"],"is_preprint":false},{"year":2017,"finding":"STRA6 activates JAK2-STAT3 signaling to promote colon cancer stem cell maintenance. Downregulation of STRA6 or RBP4 decreased cancer stem cell fraction and sphere and tumor initiation frequency. High-fat diet increased STRA6 levels and promoted tumor growth.","method":"STRA6 knockdown in colon cancer cells, sphere formation assay, xenograft tumor initiation assay, JAK2-STAT3 signaling analysis","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined stem cell and tumor phenotype, JAK2-STAT3 pathway readout, single lab","pmids":["28689994"],"is_preprint":false},{"year":2017,"finding":"Adipose tissue STRA6 undergoes circadian patterning driven in part by the nuclear transcription factor REV-ERBα. STRA6 is necessary for diurnal rhythmicity of insulin action and JAK/STAT signaling in adipose tissue.","method":"Circadian expression analysis of STRA6, REV-ERBα manipulation, adipose-specific STRA6 knockout mouse, insulin action and JAK/STAT signaling assays at different circadian time points","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with circadian insulin signaling readout, REV-ERBα regulatory link identified, single lab","pmids":["28733465"],"is_preprint":false},{"year":2021,"finding":"Ca2+-calmodulin binding to STRA6 is mediated via the BP2 intracellular helix region. At resting intracellular Ca2+ levels (<100 nM), BP2 binds only the C-lobe of calmodulin. As Ca2+ approaches 1000 nM (signaling levels), BP2 interacts with both N- and C-lobes of Ca2+-loaded calmodulin. BP2 binding increases Ca2+-binding affinity of calmodulin and slows Ca2+ dissociation rates in both lobes.","method":"NMR chemical shift perturbation mapping, isothermal titration calorimetry, kinetic Ca2+ binding studies with BP2 peptide derived from STRA6","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural mapping plus thermodynamic and kinetic binding assays, multiple orthogonal biophysical methods in single study","pmids":["34592217"],"is_preprint":false},{"year":2019,"finding":"O-GlcNAcylation of STRA6 in diabetic kidneys significantly modifies STRA6, suppresses RBP4 binding activity, and disrupts retinol signals (CRBP1, LRAT, retinol, retinoic acid, RARs). Blocking O-GlcNAcylation with OSMI-1 or OGA overexpression restored STRA6 function and retinol signals.","method":"Co-immunoprecipitation, proximity ligation assay, Western blot, HPLC retinoid measurement, OGT/OGA siRNA, TMG/OSMI-1 pharmacological manipulation in db/db and ob/ob mice and HK-2 cells","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods demonstrating O-GlcNAcylation of STRA6 and functional consequences, single lab","pmids":["30905621"],"is_preprint":false},{"year":2021,"finding":"STRA6 mediates retinol transfer from hepatic stellate cells (HSCs) to hepatocytes during liver fibrosis. TIF1γ suppression in HSCs upregulates STRA6 and promotes retinol release; hepatocytes take up retinol via STRA6, leading to lipogenesis (upregulation of lipogenesis-related genes and triglyceride accumulation). STRA6 knockdown in vivo reduced liver fibrosis.","method":"siRNA knockdown of STRA6 in LX2 cells, HepG2 retinol uptake assay, RAR antagonist, in vivo siSTRA6 treatment in TAA fibrosis model, Lrat:Cas9-ERT2:sgTif1γ mice","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined lipogenesis phenotype both in vitro and in vivo, mechanistic pathway identified, single lab","pmids":["33407858"],"is_preprint":false},{"year":2023,"finding":"STRA6 is essential for proper induction of vascular smooth muscle cell (SMC) lineages from human cardiac progenitors. STRA6-knockout hESCs could differentiate into cardiomyocytes normally but failed to differentiate into mesodermal- or neural crest-derived SMCs. A previously unrecognized interaction between RA nuclear receptors RARα/RXRα and TBX1 (an OFT-specific transcription factor) was identified as a downstream effector of STRA6-mediated RA signaling.","method":"STRA6-knockout hESC differentiation assays, population RNA-seq, co-immunoprecipitation of RARα/RXRα with TBX1, single-cell RNA-seq comparison of human and murine embryonic hearts","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout hESC model with differentiation phenotype plus Co-IP demonstrating RARα/RXRα-TBX1 interaction, single lab","pmids":["36635482"],"is_preprint":false},{"year":2022,"finding":"STRA6 is critical for adjusting the stoichiometry of chromophore and opsins in rod and cone photoreceptors. In STRA6-deficient mice, decreased chromophore led to downregulation of opsin genes in rods and absent/mislocalized opsins in cones. Rod photoreceptors entrapped available chromophore but showed significant amounts of chromophore-free opsins. Vitamin A supplementation ameliorated rod but not cone phenotype.","method":"Stra6-knockout mouse model, retinoid quantification, opsin gene expression analysis, immunolocalization of opsins, electroretinography, pharmacological vitamin A rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple biochemical, histological, and physiological readouts, pharmacological rescue experiment, replicated across rod and cone systems","pmids":["34508587"],"is_preprint":false},{"year":2024,"finding":"RBP4 promotes muscle atrophy through a STRA6-dependent JAK2/STAT3 pathway. Holo-RBP4 upregulated STRA6 expression (>3-fold) and promoted phosphorylation of JAK2 and STAT3. Inhibition of STRA6, JAK2, or STAT3 by siRNA or inhibitors decreased expression of atrophy markers Atrogin-1 and MuRF1, and decreased expression of myogenesis regulators MyoD and MyoG in holo-RBP4-treated C2C12 myotubes.","method":"siRNA knockdown of STRA6/JAK2/STAT3, specific signaling inhibitors, C2C12 myotube assays, RBP4-knockout mouse model, denervation-induced atrophy model, intramuscular injection of holo-RBP4","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway signaling readout in both in vitro and in vivo systems, single lab","pmids":["39031684"],"is_preprint":false},{"year":2024,"finding":"STRA6 interacts with integrin-linked kinase (ILK) and subsequently activates the AKT/mTOR signaling pathway in thyroid carcinoma, promoting cell proliferation and metastasis. STRA6 also reprograms lipid metabolism through SREBP1 downstream of this axis.","method":"Co-immunoprecipitation of STRA6 with ILK, RNA sequencing, STRA6 stable knockdown, in vitro proliferation/metastasis assays, xenograft model, LNP-siRNA delivery","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying ILK interaction, genetic knockdown with defined signaling and phenotypic readouts, single lab","pmids":["36592123"],"is_preprint":false},{"year":2024,"finding":"STRA6 mRNA stability is regulated by m6A modification: VIRMA (an m6A methyltransferase) targets the 3' UTR of STRA6 mRNA, and the m6A reader IGF2BP2 stabilizes STRA6 mRNA. VIRMA-driven STRA6 upregulation promotes STAT3 activation and HIF-1α-dependent glycolysis in pancreatic ductal adenocarcinoma.","method":"m6A sequencing, RNA sequencing, RIP-seq, mRNA stability assays, IGF2BP2 interaction studies, in vitro and in vivo PDAC models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-seq plus functional validation of mRNA stability, IGF2BP2 reader identified, signaling pathway downstream of STRA6 mapped, single lab","pmids":["38604311"],"is_preprint":false},{"year":2014,"finding":"STRA6 promotes Wnt/β-catenin signaling in gastric cancer. STRA6 knockdown inhibited the Wnt/β-catenin signaling pathway. STRA6 was confirmed as a direct target of miR-873, which suppresses GC tumor progression.","method":"STRA6 knockdown, Wnt/β-catenin pathway reporter assays, dual-luciferase reporter assay confirming miR-873 targeting of STRA6, rescue assays","journal":"Journal of experimental & clinical cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Wnt pathway measurement after STRA6 knockdown, single lab, no direct mechanistic reconstitution of how STRA6 activates Wnt","pmids":["31694721"],"is_preprint":false},{"year":2015,"finding":"Purified recombinant STRA6 interacts with RBP in a retinol-independent manner as determined by surface plasmon resonance, with binding data consistent with a transient interaction of 1 mole RBP per mole STRA6.","method":"Surface plasmon resonance-based binding analysis of purified STRA6-GFP produced in Pichia pastoris","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct binding assay with purified recombinant protein and defined stoichiometry, single lab","pmids":["25816144"],"is_preprint":false},{"year":2020,"finding":"STRA6 promotes NSCLC cell growth by activating JAK2/STAT3 signaling, which induces STAT3 target gene SREBP-1c expression, thereby promoting SREBP-1-mediated lipogenesis and providing energy for cancer cell growth.","method":"STRA6 knockdown in NSCLC cell lines and mouse xenograft, STAT3/SREBP-1 pathway analysis, lipid metabolism assays","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — STRA6 knockdown with signaling pathway readout, single lab, no direct mechanistic reconstitution","pmids":["39168951"],"is_preprint":false},{"year":2025,"finding":"STRA6 and melanin act synergistically to preserve the integrity of the outer blood-retinal barrier (oBRB). In albino Stra6-knockout mice, dietary vitamin A via chylomicrons failed to compensate for the loss of RBP4-mediated transport, leading to functional impairment of rod and cone responses and downregulation of tight junction proteins (ZO-1, Claudin-1, Claudin-3). Treatment with the pan-RAR agonist TTNPB restored junctional gene expression and oBRB function, demonstrating that barrier failure arises from impaired retinoid signaling.","method":"Albino Stra6-knockout mouse model, retinoid quantification, tight junction protein Western blot and immunofluorescence, electroretinography, TTNPB pharmacological rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple biochemical, structural, and physiological readouts plus pharmacological rescue establishing mechanism, single lab","pmids":["41135684"],"is_preprint":false},{"year":2024,"finding":"In STRA6-deficient mice, light-induced loss of ocular retinoids and visual impairment were correlated with generation of visual cycle byproducts (9-cis-retinal, 13-cis-retinal). 9-cis-retinal was recycled to all-trans-retinal via isorhodopsin. The absence of STRA6 impaired replenishment of retinoids lost through these chemical side reactions.","method":"Stra6-knockout mouse model, light bleaching experiments, HPLC retinoid quantification, rhodopsin spectrophotometry, electroretinography","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with biochemical and physiological readouts identifying role in visual cycle retinoid replenishment, single lab","pmids":["38395306"],"is_preprint":false},{"year":2014,"finding":"An alternative downstream promoter of Stra6 contains a half-site RA response element (RARE) required for RA-induced transcription. CRISPR-Cas9 editing of the endogenous RARE abolished RA-induced transcription of both Stra6 isoforms. RARγ and RXRα bind the Stra6 RARE; RA increases co-activator p300 binding and H3K27 acetylation while decreasing Suz12 and H3K27 trimethylation at both promoters, and these epigenetic changes depend on RARγ.","method":"CRISPR-Cas9 genome editing of endogenous RARE, ChIP-seq for RARγ/RXRα/p300/Suz12, luciferase reporter assay, analysis of RARγ-null mice and vitamin A-deficient mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — CRISPR-Cas9 functional validation of RARE, ChIP for transcription factors and histone marks, genetic mouse models, multiple orthogonal methods in single lab","pmids":["25544292"],"is_preprint":false},{"year":2001,"finding":"Stra6 is synergistically induced by Wnt-1 signaling and retinoic acid in mammary cells. Wnt-1 upregulates retinoic acid receptor-gamma (RAR-gamma), which partly explains this synergy. Treatment of human colorectal cancer cell lines with retinoic acid led to accumulation of Stra6 protein at the cell membrane.","method":"mRNA screening of Wnt-1-stimulated C57MG cells, retinoic acid treatment of colorectal cancer cell lines, RAR-gamma upregulation analysis","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression analysis with some mechanistic inference (RAR-gamma), single lab, no direct mechanistic reconstitution","pmids":["11358845"],"is_preprint":false}],"current_model":"STRA6 is a polytopic transmembrane homodimer (9 transmembrane + 1 intramembrane helix per protomer) that serves as the high-affinity cell-surface receptor for holo-retinol-binding protein (RBP4) and catalyzes bidirectional, facilitated retinol transport—driving vitamin A influx when coupled to intracellular acceptors CRBP-I or LRAT, and efflux into apo-RBP—while simultaneously functioning as a ligand-activated cytokine receptor that, upon retinol translocation to CRBP-I, becomes phosphorylated and activates a JAK2/STAT3/STAT5 signaling cascade; calmodulin is constitutively bound to STRA6 via its intracellular BP2 helix in a Ca2+-regulated manner that may modulate transport; the transporter is essential for vitamin A homeostasis at blood-tissue barriers (especially in the eye, brain, and testis), is required for visual chromophore stoichiometry and outer blood-retinal barrier integrity, and its signaling output—regulated by transthyretin, TTR, LRAT, O-GlcNAcylation, circadian clock factor REV-ERBα, and intracellular retinoid metabolism—controls diverse processes including insulin sensitivity, adipogenesis, cell survival via p53/apoptosis, and cardiogenesis through induction of vascular smooth muscle lineages."},"narrative":{"mechanistic_narrative":"STRA6 is a polytopic plasma-membrane protein that serves as the cell-surface receptor for circulating holo-retinol-binding protein (RBP4) and catalyzes facilitated, bidirectional retinol transport across blood-tissue barriers, coupling vitamin A homeostasis to retinoic acid signaling [PMID:18316031, PMID:22815070, PMID:24852372]. Cryo-EM of zebrafish STRA6 established a homodimer of protomers each containing nine transmembrane and one intramembrane helix, with an arch-like RBP-binding surface covering a deep lipophilic cleft open to the bilayer, supporting retinol internalization by diffusion into the membrane; calmodulin is tightly bound in a noncanonical arrangement [PMID:27563101], an interaction mediated by the intracellular BP2 helix in a Ca2+-dependent manner [PMID:34592217]. Directionality is set by intracellular acceptors: influx from holo-RBP requires coupling to CRBP-I or to lecithin:retinol acyltransferase (LRAT)-driven esterification, while apo-RBP drives efflux of free retinol [PMID:22815070, PMID:23959802]. Beyond transport, STRA6 functions as a ligand-activated cytokine receptor whose phosphorylation and JAK2/STAT3/STAT5 signaling are triggered specifically by retinol translocation into CRBP-I, making transport and signaling interdependent [PMID:22665496, PMID:25237067]. This signaling arm couples circulating RBP4 to insulin action and is suppressed by transthyretin, which blocks holo-RBP association with STRA6 [PMID:22826435, PMID:24036882, PMID:23839944]. STRA6 transcription is directly RA-inducible through a RARE bound by RARγ/RXRα with accompanying p300/H3K27ac changes [PMID:25544292]. The transporter is essential for ocular vitamin A uptake, visual chromophore/opsin stoichiometry, and outer blood-retinal barrier integrity, and for retinoid supply to brain and testis under dietary limitation [PMID:24852372, PMID:34508587, PMID:27189978, PMID:41135684]. Loss-of-function STRA6 mutations cause colobomatous microphthalmia, with mislocalizing mutants showing abolished uptake activity [PMID:17273977, PMID:21901792]. STRA6-dependent RA signaling additionally drives vascular smooth muscle lineage induction during cardiogenesis via an RARα/RXRα–TBX1 interaction [PMID:36635482], and its JAK/STAT and ILK/AKT-mTOR outputs promote proliferation, lipogenesis, and survival across multiple cancers [PMID:28689994, PMID:36592123, PMID:23449393].","teleology":[{"year":1997,"claim":"Established STRA6 as a novel hydrophobic membrane protein concentrated at blood-organ barriers and under retinoid-receptor control, framing it as candidate retinoid transport machinery.","evidence":"Subtractive hybridization cloning and in situ hybridization in RAR-alpha null mice","pmids":["9203140"],"confidence":"Medium","gaps":["No biochemical transport activity demonstrated","No direct ligand or partner identified"]},{"year":2001,"claim":"Linked Stra6 expression to combined Wnt and RA inputs, hinting at transcriptional integration of developmental signals at the STRA6 locus.","evidence":"mRNA screening in Wnt-1-stimulated mammary cells and RA-treated colorectal lines","pmids":["11358845"],"confidence":"Low","gaps":["Correlative expression only; no mechanism of Wnt-RA synergy reconstituted","STRA6 protein function not addressed"]},{"year":2007,"claim":"Tied STRA6 loss-of-function to human disease and pinpointed functional residues, establishing topology-critical loop and C-terminal signaling motifs.","evidence":"Homozygosity mapping, mutational analysis, and topology modeling in patients","pmids":["17273977"],"confidence":"Medium","gaps":["No in vitro reconstitution of mutant transport defects","SH2/phospho-motif function inferred from sequence, not assayed"]},{"year":2008,"claim":"Demonstrated that STRA6 mediates bidirectional retinol transfer from RBP4 into cells, enhanced by LRAT, and is required for vitamin A delivery to the developing eye.","evidence":"Cell-based retinol transfer assays with LRAT and zebrafish morpholino knockdown","pmids":["18316031"],"confidence":"High","gaps":["Mechanism of coupling to intracellular acceptors not yet resolved","Signaling function not addressed"]},{"year":2012,"claim":"Reconstituted STRA6 catalytic logic and showed transport and signaling are interdependent: retinol translocation to CRBP-I, not mere holo-RBP binding, triggers STRA6 phosphorylation and JAK/STAT signaling, and phosphorylation is required for uptake.","evidence":"In vitro transport assays with purified components, phosphorylation-deficient mutants, CRBP-I coupling, and TTR competition assays with mouse insulin-resistance models","pmids":["22815070","22665496","22826435"],"confidence":"High","gaps":["Identity of the kinase phosphorylating STRA6 not defined","Structural basis of signaling-competent state unknown"]},{"year":2013,"claim":"Defined STRA6's primary systemic role as coupling circulating holo-RBP to JAK/STAT signaling that suppresses insulin action, with retinol delivery dispensable outside the eye, and showed LRAT-dependent esterification drives the inward transport that activates signaling.","evidence":"Stra6-null and LRAT-null mouse models, HPLC retinoid quantification, JAK2/STAT5 assays, glucose tolerance tests; adipocyte differentiation and oncogenic transformation/xenograft assays","pmids":["23839944","24036882","23959802","25237067"],"confidence":"High","gaps":["Why eye retinoid homeostasis is uniquely STRA6-dependent unexplained at this stage","Tissue-specific signaling outputs not fully mapped"]},{"year":2013,"claim":"Identified a retinoid-independent, p53-driven pro-apoptotic role for STRA6 acting via mitochondrial depolarization and ROS, broadening its function beyond retinoid transport/signaling.","evidence":"DNA damage and p53-dependent transcription assays, ROS and mitochondrial membrane potential measurements with Stra6 knockdown","pmids":["23449393"],"confidence":"Medium","gaps":["Molecular mechanism linking STRA6 to mitochondria undefined","How a plasma-membrane transporter drives ROS unclear"]},{"year":2014,"claim":"Cemented STRA6 as a bona fide ocular vitamin A transporter and dissected the RA-responsive promoter, showing knockout causes RPE/choroid malformation and cone death, and that an endogenous RARE bound by RARγ/RXRα controls its RA-induced transcription.","evidence":"Stra6-knockout mice (HPLC, ERG, histology, rescue), G304K mislocalization assays, zebrafish RA-inhibition models, CRISPR editing of the RARE plus ChIP-seq","pmids":["24852372","21901792","25544292"],"confidence":"High","gaps":["Mechanism of STRA6 trafficking to the membrane not detailed","Cone-specific vulnerability mechanism unresolved"]},{"year":2016,"claim":"Provided the structural foundation—a homodimer with a lipophilic cleft open to the membrane and tightly bound calmodulin—rationalizing retinol release into the bilayer and RBP docking, and confirmed STRA6's barrier role in eye, brain, and testis.","evidence":"3.9 Å cryo-EM of zebrafish STRA6 with RBP-binding residue mapping; Stra6-knockout mice under dietary vitamin A control with multi-tissue retinoid quantification","pmids":["27563101","27189978"],"confidence":"High","gaps":["Conformational cycle of transport not captured","Functional role of bound calmodulin not established structurally"]},{"year":2017,"claim":"Extended STRA6 signaling to metabolic and oncogenic contexts—β-cell insulin synthesis via JAK2/STAT1/ISL-1, circadian insulin action via REV-ERBα, and colon cancer stem cell maintenance via JAK2/STAT3.","evidence":"Islet/INS-1E and RBP4-transgenic models, adipose-specific Stra6 knockout with circadian profiling, colon cancer knockdown with sphere/tumor-initiation assays","pmids":["33199363","28733465","28689994"],"confidence":"Medium","gaps":["Tissue specificity of STAT effector usage unexplained","Direct connection of circadian regulation to transport vs signaling unclear"]},{"year":2021,"claim":"Resolved how calmodulin engages STRA6—via the BP2 helix in a Ca2+-tunable bilobal manner—and showed STRA6-mediated retinol transfer between hepatic stellate cells and hepatocytes drives fibrogenic lipogenesis.","evidence":"NMR/ITC/kinetic analysis of BP2-calmodulin binding; STRA6 knockdown in vitro and in vivo fibrosis models with TIF1γ manipulation","pmids":["34592217","33407858"],"confidence":"Medium","gaps":["Functional effect of Ca2+-calmodulin on transport not directly demonstrated","How interorgan retinol shuttling is triggered in fibrosis unresolved"]},{"year":2022,"claim":"Showed STRA6 controls chromophore/opsin stoichiometry in photoreceptors and replenishes retinoids lost to visual-cycle side reactions, explaining the differential rod versus cone dependence on vitamin A.","evidence":"Stra6-knockout mice with retinoid quantification, opsin expression/immunolocalization, light-bleaching, and vitamin A rescue","pmids":["34508587","38395306"],"confidence":"High","gaps":["Why cone phenotype resists vitamin A supplementation unexplained","Quantitative flux of byproduct recycling not defined"]},{"year":2023,"claim":"Established STRA6 as required for vascular smooth muscle lineage induction from human cardiac progenitors, acting through an RARα/RXRα–TBX1 transcriptional interaction.","evidence":"STRA6-knockout hESC differentiation, RNA-seq, RARα/RXRα-TBX1 Co-IP, cross-species scRNA-seq","pmids":["36635482"],"confidence":"Medium","gaps":["Direct transcriptional targets of the RAR-TBX1 complex not enumerated","Whether transport or signaling activity is the relevant STRA6 function not distinguished"]},{"year":2024,"claim":"Expanded STRA6's disease roles—RBP4/STRA6/JAK2/STAT3-driven muscle atrophy, ILK/AKT-mTOR/SREBP1 signaling in thyroid carcinoma, and m6A-mediated (VIRMA/IGF2BP2) STRA6 mRNA stabilization driving glycolysis in pancreatic cancer.","evidence":"C2C12/RBP4-knockout and denervation models; STRA6-ILK Co-IP with knockdown/xenograft; m6A-seq, RIP-seq, and mRNA stability assays in PDAC","pmids":["39031684","36592123","38604311"],"confidence":"Medium","gaps":["Whether ILK binding is direct and how it relates to JAK/STAT arm unclear","Generalizability of STRA6-driven lipogenesis across tumor types untested"]},{"year":2025,"claim":"Mechanistically linked STRA6 loss to outer blood-retinal barrier failure via impaired retinoid signaling, showing RAR agonist rescues tight-junction gene expression and barrier function.","evidence":"Albino Stra6-knockout mice with retinoid quantification, tight-junction protein analysis, ERG, and TTNPB pharmacological rescue","pmids":["41135684"],"confidence":"High","gaps":["Synergy mechanism between melanin and STRA6 not molecularly defined","Which RA-target genes directly maintain junctions not pinpointed"]},{"year":null,"claim":"How STRA6 mechanically couples retinol translocation to its phosphorylation-dependent switch into a JAK/STAT-competent receptor—and what role bound calmodulin plays in gating transport—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of a signaling-active or substrate-bound human STRA6 conformer","Functional consequence of Ca2+-calmodulin binding on transport untested","Kinase responsible for STRA6 phosphorylation unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,5,8,11]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[5,8]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[3,7,27]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[12,13,32]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,5,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[21,11]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[22,30,29]}],"complexes":[],"partners":["RBP4","CRBP1","LRAT","TTR","JAK2","CALM1","ILK","IGF2BP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BX79","full_name":"Receptor for retinol uptake STRA6","aliases":["Retinol-binding protein receptor STRA6","Stimulated by retinoic acid gene 6 protein homolog"],"length_aa":667,"mass_kda":73.5,"function":"Functions as a retinol transporter. 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\"finding\": \"STRA6 was identified as a novel multi-transmembrane integral membrane protein. Structural analysis of missense mutations (P90L, P293L, T321P) suggested significant effects on the geometry of loops connecting transmembrane helices. Two C-terminal variations (T644M and R655C) alter an SH2-binding motif and a phosphorylation site, respectively, indicating these are functional sites.\",\n      \"method\": \"Homozygosity mapping, mutational analysis, structural modeling of transmembrane topology\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — structural modeling plus loss-of-function (protein absent in patient fibroblasts), single lab, multiple mutations analyzed but no in vitro reconstitution\",\n      \"pmids\": [\"17273977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"STRA6 encodes a highly hydrophobic membrane protein of a new type with no similarity to previously characterized integral membrane proteins. It is strongly expressed at blood-organ barriers (e.g., blood-testis barrier in Sertoli cells) with a spermatogenic cycle-dependent expression that is lost in RAR-alpha null mutants, suggesting it is a component of a retinoid transport machinery.\",\n      \"method\": \"Subtractive hybridization cDNA cloning, in situ hybridization, analysis of RAR-alpha null mutants\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — original identification by expression cloning and genetic model (RAR-alpha null), multiple tissues examined, single lab\",\n      \"pmids\": [\"9203140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STRA6-dependent transfer of retinol from RBP4 into NIH 3T3 fibroblasts was enhanced by lecithin:retinol acyltransferase (LRAT). Retinol transfer was shown to be bidirectional, establishing that STRA6 acts as a retinol channel/transporter. Loss-of-function in zebrafish revealed that Stra6 deficiency caused vitamin A deprivation of developing eyes. In the absence of Stra6, holo-Rbp4 provoked non-specific vitamin A excess in embryonic tissues, impairing retinoic acid receptor signaling.\",\n      \"method\": \"Cell-based retinol transfer assay with LRAT co-expression, zebrafish morpholino knockdown, pharmacological and morpholino RBP4 reduction\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-based transport assay plus genetic loss-of-function in zebrafish with multiple phenotypic readouts, replicated across in vitro and in vivo systems\",\n      \"pmids\": [\"18316031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STRA6 functions as both a retinol transporter and a cytokine receptor. Activation of STRA6 signaling (JAK/STAT cascade) is triggered not simply by holo-RBP binding but by STRA6-mediated translocation of retinol from serum RBP to the intracellular acceptor CRBP-I. STRA6 phosphorylation is required for retinol uptake to proceed, demonstrating that signaling and transport are critically interdependent.\",\n      \"method\": \"Phosphorylation assays, CRBP-I interaction studies, retinol uptake assays with phosphorylation-deficient STRA6 mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of phosphorylation sites, retinol transport assay, JAK/STAT signaling readout, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"22665496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Transthyretin (TTR) blocks the ability of holo-RBP to associate with STRA6, thereby suppressing both STRA6-mediated retinol uptake and STRA6-initiated JAK/STAT cell signaling. TTR protects mice from RBP-induced insulin resistance. STRA6 functions only when plasma RBP levels exceed TTR levels.\",\n      \"method\": \"Cell-based retinol uptake assay, JAK/STAT signaling assays, glucose tolerance tests in mice with TTR manipulation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding competition assay, in vivo insulin resistance model, multiple readouts in single lab\",\n      \"pmids\": [\"22826435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STRA6 catalyzes bidirectional retinol transport: (1) influx — retinol release from holo-RBP coupled to CRBP-I or LRAT; (2) efflux — loading of free retinol into apo-RBP, driven by CRBP-I. Holo-RBP blocks STRA6-mediated efflux by competing with apo-RBP binding. STRA6 also catalyzes efficient retinol exchange between intracellular CRBP-I and extracellular RBP.\",\n      \"method\": \"In vitro retinol transport assays with purified components, competition binding assays\",\n      \"journal\": \"The Journal of membrane biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted transport assay demonstrating multiple catalytic activities, single lab with multiple orthogonal transport readouts\",\n      \"pmids\": [\"22815070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lecithin:retinol acyl transferase (LRAT), which esterifies retinol to retinyl esters, is necessary for activation of the STRA6/JAK2/STAT5 signaling cascade by holo-RBP. LRAT-null mice are protected from holo-RBP-induced suppression of insulin responses, establishing that STRA6 signaling requires retinol esterification to drive inward transport.\",\n      \"method\": \"LRAT-null mouse model, JAK2/STAT5 phosphorylation assays, insulin response measurements\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null mouse model plus biochemical signaling assays, two orthogonal methods in single lab\",\n      \"pmids\": [\"24036882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STRA6 functions as a cytokine receptor activating JAK2 and the transcription factors STAT3 and STAT5 upon holo-RBP binding. This signaling promotes oncogenic transformation and is critical for tumor formation by colon carcinoma cells in vivo.\",\n      \"method\": \"JAK2/STAT3/STAT5 phosphorylation assays, oncogenic transformation assay in fibroblasts, xenograft mouse model with STRA6 knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro signaling assays and in vivo xenograft model, single lab with two orthogonal methods\",\n      \"pmids\": [\"25237067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STRA6 mediates bidirectional retinol transport in adipocyte precursors: holo-RBP4 triggers retinol influx and blocks adipocyte differentiation by activating RARα, while apo-RBP4 triggers retinol efflux, reducing cellular retinoids and RARα activity, thereby enhancing adipogenesis. Ectopic STRA6 synergized with apo-RBP4 to enhance adipogenesis.\",\n      \"method\": \"Cell-based retinol efflux/influx assays, RARα reporter assays, adipocyte differentiation assays, mouse liver RBP4 mobilization experiment\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional transport reconstituted in cell culture, RARα activity measured, adipocyte differentiation readout, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23959802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STRA6 is essential for RBP-induced suppression of insulin signaling in vivo; Stra6-null mice are protected from RBP-induced insulin resistance. However, with the exception of the eye, ablation of Stra6 had only a modest effect on retinoid homeostasis in other tissues, demonstrating that STRA6's primary systemic function (outside the eye) is coupling circulating holo-RBP to JAK/STAT cell signaling rather than retinol delivery.\",\n      \"method\": \"Stra6-null mouse model, retinoid quantification by HPLC, insulin signaling assays, glucose tolerance tests\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mouse with multiple phenotypic readouts (retinoid homeostasis, insulin signaling, glucose tolerance), replicated across tissues, single lab\",\n      \"pmids\": [\"23839944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Stra6 can be upregulated by DNA damage in a p53-dependent manner and plays a role in p53-induced apoptosis. Stra6 expression induced mitochondrial depolarization and accumulation of reactive oxygen species; inhibition of Stra6 compromised p53-induced apoptosis. These functions did not require downstream activation of retinoic acid signaling.\",\n      \"method\": \"DNA damage assays, p53-dependent transcriptional analysis, apoptosis assays, ROS measurement, mitochondrial membrane potential assay, Stra6 knockdown\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined apoptotic phenotype, multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"23449393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STRA6 is a bona fide vitamin A transporter critical for ocular vitamin A uptake. Stra6-knockout mice show markedly reduced ocular retinoids, malformations in the choroid and RPE, early cone photoreceptor cell death, and reduced rod outer segment length. STRA6-mediated uptake in the eye is a regulated process mandatory when RBP4 is the only transport mode. Vitamin A transport through the blood-CSF barrier in the choroid plexus was also impaired.\",\n      \"method\": \"Stra6-knockout mouse model, HPLC retinoid quantification, ophthalmic imaging, histology, electroretinography, pharmacological vitamin A rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal readouts (biochemical, histological, physiological, pharmacological rescue), replicated in multiple tissues\",\n      \"pmids\": [\"24852372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The STRA6 G304K mutant protein is mislocalized and has severely reduced vitamin A uptake activity, establishing that membrane localization is required for STRA6 function. Inhibiting retinoic acid synthesis in zebrafish reproduced the colobomatous microanophthalmia phenotype, confirming diminished RA levels underlie the eye malformations.\",\n      \"method\": \"STRA6 G304K mutant expression and localization analysis, retinol uptake assay, zebrafish RA synthesis inhibition model\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional uptake assay plus localization study plus zebrafish disease model, single lab\",\n      \"pmids\": [\"21901792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cryo-EM structure of zebrafish STRA6 determined at 3.9 Å resolution revealed: (1) STRA6 has one intramembrane and nine transmembrane helices in a homodimeric assembly; (2) calmodulin is tightly bound to STRA6 in a noncanonical arrangement; (3) residues involved in RBP binding map to an arch-like structure covering a deep lipophilic cleft; (4) the cleft is open to the membrane, suggesting retinol internalization via direct diffusion into the lipid bilayer.\",\n      \"method\": \"Single-particle cryo-electron microscopy at 3.9 Å resolution\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structure determination by cryo-EM with functional mapping, foundational structural study providing mechanistic insight into transport and binding\",\n      \"pmids\": [\"27563101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STRA6 is critical for vitamin A transport across blood-tissue barriers in the eyes, brain, and testis. In Stra6-knockout mice under vitamin A-deficient conditions, retinoid homeostasis in the eye, brain, and testis (but not in fat or lung) was severely impaired. Stra6 expression in testis and brain was regulated by vitamin A supply, reducing consumption when dietary supply was limited.\",\n      \"method\": \"Stra6-knockout mouse model with controlled dietary vitamin A, retinoid quantification in multiple tissues, retinoid-dependent physiological assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with dietary manipulation and multi-tissue biochemical analysis, multiple orthogonal readouts\",\n      \"pmids\": [\"27189978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STRA6 mediates the inhibitory effect of RBP4 on insulin synthesis in pancreatic β-cells through the JAK2/STAT1/ISL-1 signaling pathway. STRA6 is expressed in β-cells and its activation by RBP4 suppresses glucose-stimulated insulin secretion.\",\n      \"method\": \"Primary islet isolation, INS-1E cell culture, RBP4 transgenic mouse model, JAK2/STAT1/ISL-1 pathway analysis, siRNA knockdown of STRA6\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model plus cell-based STRA6 knockdown with defined signaling pathway readout, single lab\",\n      \"pmids\": [\"33199363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STRA6 activates JAK2-STAT3 signaling to promote colon cancer stem cell maintenance. Downregulation of STRA6 or RBP4 decreased cancer stem cell fraction and sphere and tumor initiation frequency. High-fat diet increased STRA6 levels and promoted tumor growth.\",\n      \"method\": \"STRA6 knockdown in colon cancer cells, sphere formation assay, xenograft tumor initiation assay, JAK2-STAT3 signaling analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined stem cell and tumor phenotype, JAK2-STAT3 pathway readout, single lab\",\n      \"pmids\": [\"28689994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adipose tissue STRA6 undergoes circadian patterning driven in part by the nuclear transcription factor REV-ERBα. STRA6 is necessary for diurnal rhythmicity of insulin action and JAK/STAT signaling in adipose tissue.\",\n      \"method\": \"Circadian expression analysis of STRA6, REV-ERBα manipulation, adipose-specific STRA6 knockout mouse, insulin action and JAK/STAT signaling assays at different circadian time points\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with circadian insulin signaling readout, REV-ERBα regulatory link identified, single lab\",\n      \"pmids\": [\"28733465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ca2+-calmodulin binding to STRA6 is mediated via the BP2 intracellular helix region. At resting intracellular Ca2+ levels (<100 nM), BP2 binds only the C-lobe of calmodulin. As Ca2+ approaches 1000 nM (signaling levels), BP2 interacts with both N- and C-lobes of Ca2+-loaded calmodulin. BP2 binding increases Ca2+-binding affinity of calmodulin and slows Ca2+ dissociation rates in both lobes.\",\n      \"method\": \"NMR chemical shift perturbation mapping, isothermal titration calorimetry, kinetic Ca2+ binding studies with BP2 peptide derived from STRA6\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural mapping plus thermodynamic and kinetic binding assays, multiple orthogonal biophysical methods in single study\",\n      \"pmids\": [\"34592217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"O-GlcNAcylation of STRA6 in diabetic kidneys significantly modifies STRA6, suppresses RBP4 binding activity, and disrupts retinol signals (CRBP1, LRAT, retinol, retinoic acid, RARs). Blocking O-GlcNAcylation with OSMI-1 or OGA overexpression restored STRA6 function and retinol signals.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, Western blot, HPLC retinoid measurement, OGT/OGA siRNA, TMG/OSMI-1 pharmacological manipulation in db/db and ob/ob mice and HK-2 cells\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods demonstrating O-GlcNAcylation of STRA6 and functional consequences, single lab\",\n      \"pmids\": [\"30905621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STRA6 mediates retinol transfer from hepatic stellate cells (HSCs) to hepatocytes during liver fibrosis. TIF1γ suppression in HSCs upregulates STRA6 and promotes retinol release; hepatocytes take up retinol via STRA6, leading to lipogenesis (upregulation of lipogenesis-related genes and triglyceride accumulation). STRA6 knockdown in vivo reduced liver fibrosis.\",\n      \"method\": \"siRNA knockdown of STRA6 in LX2 cells, HepG2 retinol uptake assay, RAR antagonist, in vivo siSTRA6 treatment in TAA fibrosis model, Lrat:Cas9-ERT2:sgTif1γ mice\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined lipogenesis phenotype both in vitro and in vivo, mechanistic pathway identified, single lab\",\n      \"pmids\": [\"33407858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STRA6 is essential for proper induction of vascular smooth muscle cell (SMC) lineages from human cardiac progenitors. STRA6-knockout hESCs could differentiate into cardiomyocytes normally but failed to differentiate into mesodermal- or neural crest-derived SMCs. A previously unrecognized interaction between RA nuclear receptors RARα/RXRα and TBX1 (an OFT-specific transcription factor) was identified as a downstream effector of STRA6-mediated RA signaling.\",\n      \"method\": \"STRA6-knockout hESC differentiation assays, population RNA-seq, co-immunoprecipitation of RARα/RXRα with TBX1, single-cell RNA-seq comparison of human and murine embryonic hearts\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout hESC model with differentiation phenotype plus Co-IP demonstrating RARα/RXRα-TBX1 interaction, single lab\",\n      \"pmids\": [\"36635482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STRA6 is critical for adjusting the stoichiometry of chromophore and opsins in rod and cone photoreceptors. In STRA6-deficient mice, decreased chromophore led to downregulation of opsin genes in rods and absent/mislocalized opsins in cones. Rod photoreceptors entrapped available chromophore but showed significant amounts of chromophore-free opsins. Vitamin A supplementation ameliorated rod but not cone phenotype.\",\n      \"method\": \"Stra6-knockout mouse model, retinoid quantification, opsin gene expression analysis, immunolocalization of opsins, electroretinography, pharmacological vitamin A rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple biochemical, histological, and physiological readouts, pharmacological rescue experiment, replicated across rod and cone systems\",\n      \"pmids\": [\"34508587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBP4 promotes muscle atrophy through a STRA6-dependent JAK2/STAT3 pathway. Holo-RBP4 upregulated STRA6 expression (>3-fold) and promoted phosphorylation of JAK2 and STAT3. Inhibition of STRA6, JAK2, or STAT3 by siRNA or inhibitors decreased expression of atrophy markers Atrogin-1 and MuRF1, and decreased expression of myogenesis regulators MyoD and MyoG in holo-RBP4-treated C2C12 myotubes.\",\n      \"method\": \"siRNA knockdown of STRA6/JAK2/STAT3, specific signaling inhibitors, C2C12 myotube assays, RBP4-knockout mouse model, denervation-induced atrophy model, intramuscular injection of holo-RBP4\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway signaling readout in both in vitro and in vivo systems, single lab\",\n      \"pmids\": [\"39031684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STRA6 interacts with integrin-linked kinase (ILK) and subsequently activates the AKT/mTOR signaling pathway in thyroid carcinoma, promoting cell proliferation and metastasis. STRA6 also reprograms lipid metabolism through SREBP1 downstream of this axis.\",\n      \"method\": \"Co-immunoprecipitation of STRA6 with ILK, RNA sequencing, STRA6 stable knockdown, in vitro proliferation/metastasis assays, xenograft model, LNP-siRNA delivery\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying ILK interaction, genetic knockdown with defined signaling and phenotypic readouts, single lab\",\n      \"pmids\": [\"36592123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STRA6 mRNA stability is regulated by m6A modification: VIRMA (an m6A methyltransferase) targets the 3' UTR of STRA6 mRNA, and the m6A reader IGF2BP2 stabilizes STRA6 mRNA. VIRMA-driven STRA6 upregulation promotes STAT3 activation and HIF-1α-dependent glycolysis in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"m6A sequencing, RNA sequencing, RIP-seq, mRNA stability assays, IGF2BP2 interaction studies, in vitro and in vivo PDAC models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-seq plus functional validation of mRNA stability, IGF2BP2 reader identified, signaling pathway downstream of STRA6 mapped, single lab\",\n      \"pmids\": [\"38604311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STRA6 promotes Wnt/β-catenin signaling in gastric cancer. STRA6 knockdown inhibited the Wnt/β-catenin signaling pathway. STRA6 was confirmed as a direct target of miR-873, which suppresses GC tumor progression.\",\n      \"method\": \"STRA6 knockdown, Wnt/β-catenin pathway reporter assays, dual-luciferase reporter assay confirming miR-873 targeting of STRA6, rescue assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Wnt pathway measurement after STRA6 knockdown, single lab, no direct mechanistic reconstitution of how STRA6 activates Wnt\",\n      \"pmids\": [\"31694721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Purified recombinant STRA6 interacts with RBP in a retinol-independent manner as determined by surface plasmon resonance, with binding data consistent with a transient interaction of 1 mole RBP per mole STRA6.\",\n      \"method\": \"Surface plasmon resonance-based binding analysis of purified STRA6-GFP produced in Pichia pastoris\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding assay with purified recombinant protein and defined stoichiometry, single lab\",\n      \"pmids\": [\"25816144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STRA6 promotes NSCLC cell growth by activating JAK2/STAT3 signaling, which induces STAT3 target gene SREBP-1c expression, thereby promoting SREBP-1-mediated lipogenesis and providing energy for cancer cell growth.\",\n      \"method\": \"STRA6 knockdown in NSCLC cell lines and mouse xenograft, STAT3/SREBP-1 pathway analysis, lipid metabolism assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — STRA6 knockdown with signaling pathway readout, single lab, no direct mechanistic reconstitution\",\n      \"pmids\": [\"39168951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STRA6 and melanin act synergistically to preserve the integrity of the outer blood-retinal barrier (oBRB). In albino Stra6-knockout mice, dietary vitamin A via chylomicrons failed to compensate for the loss of RBP4-mediated transport, leading to functional impairment of rod and cone responses and downregulation of tight junction proteins (ZO-1, Claudin-1, Claudin-3). Treatment with the pan-RAR agonist TTNPB restored junctional gene expression and oBRB function, demonstrating that barrier failure arises from impaired retinoid signaling.\",\n      \"method\": \"Albino Stra6-knockout mouse model, retinoid quantification, tight junction protein Western blot and immunofluorescence, electroretinography, TTNPB pharmacological rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple biochemical, structural, and physiological readouts plus pharmacological rescue establishing mechanism, single lab\",\n      \"pmids\": [\"41135684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In STRA6-deficient mice, light-induced loss of ocular retinoids and visual impairment were correlated with generation of visual cycle byproducts (9-cis-retinal, 13-cis-retinal). 9-cis-retinal was recycled to all-trans-retinal via isorhodopsin. The absence of STRA6 impaired replenishment of retinoids lost through these chemical side reactions.\",\n      \"method\": \"Stra6-knockout mouse model, light bleaching experiments, HPLC retinoid quantification, rhodopsin spectrophotometry, electroretinography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with biochemical and physiological readouts identifying role in visual cycle retinoid replenishment, single lab\",\n      \"pmids\": [\"38395306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"An alternative downstream promoter of Stra6 contains a half-site RA response element (RARE) required for RA-induced transcription. CRISPR-Cas9 editing of the endogenous RARE abolished RA-induced transcription of both Stra6 isoforms. RARγ and RXRα bind the Stra6 RARE; RA increases co-activator p300 binding and H3K27 acetylation while decreasing Suz12 and H3K27 trimethylation at both promoters, and these epigenetic changes depend on RARγ.\",\n      \"method\": \"CRISPR-Cas9 genome editing of endogenous RARE, ChIP-seq for RARγ/RXRα/p300/Suz12, luciferase reporter assay, analysis of RARγ-null mice and vitamin A-deficient mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — CRISPR-Cas9 functional validation of RARE, ChIP for transcription factors and histone marks, genetic mouse models, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"25544292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Stra6 is synergistically induced by Wnt-1 signaling and retinoic acid in mammary cells. Wnt-1 upregulates retinoic acid receptor-gamma (RAR-gamma), which partly explains this synergy. Treatment of human colorectal cancer cell lines with retinoic acid led to accumulation of Stra6 protein at the cell membrane.\",\n      \"method\": \"mRNA screening of Wnt-1-stimulated C57MG cells, retinoic acid treatment of colorectal cancer cell lines, RAR-gamma upregulation analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression analysis with some mechanistic inference (RAR-gamma), single lab, no direct mechanistic reconstitution\",\n      \"pmids\": [\"11358845\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STRA6 is a polytopic transmembrane homodimer (9 transmembrane + 1 intramembrane helix per protomer) that serves as the high-affinity cell-surface receptor for holo-retinol-binding protein (RBP4) and catalyzes bidirectional, facilitated retinol transport—driving vitamin A influx when coupled to intracellular acceptors CRBP-I or LRAT, and efflux into apo-RBP—while simultaneously functioning as a ligand-activated cytokine receptor that, upon retinol translocation to CRBP-I, becomes phosphorylated and activates a JAK2/STAT3/STAT5 signaling cascade; calmodulin is constitutively bound to STRA6 via its intracellular BP2 helix in a Ca2+-regulated manner that may modulate transport; the transporter is essential for vitamin A homeostasis at blood-tissue barriers (especially in the eye, brain, and testis), is required for visual chromophore stoichiometry and outer blood-retinal barrier integrity, and its signaling output—regulated by transthyretin, TTR, LRAT, O-GlcNAcylation, circadian clock factor REV-ERBα, and intracellular retinoid metabolism—controls diverse processes including insulin sensitivity, adipogenesis, cell survival via p53/apoptosis, and cardiogenesis through induction of vascular smooth muscle lineages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STRA6 is a polytopic plasma-membrane protein that serves as the cell-surface receptor for circulating holo-retinol-binding protein (RBP4) and catalyzes facilitated, bidirectional retinol transport across blood-tissue barriers, coupling vitamin A homeostasis to retinoic acid signaling [#2, #5, #11]. Cryo-EM of zebrafish STRA6 established a homodimer of protomers each containing nine transmembrane and one intramembrane helix, with an arch-like RBP-binding surface covering a deep lipophilic cleft open to the bilayer, supporting retinol internalization by diffusion into the membrane; calmodulin is tightly bound in a noncanonical arrangement [#13], an interaction mediated by the intracellular BP2 helix in a Ca2+-dependent manner [#18]. Directionality is set by intracellular acceptors: influx from holo-RBP requires coupling to CRBP-I or to lecithin:retinol acyltransferase (LRAT)-driven esterification, while apo-RBP drives efflux of free retinol [#5, #8]. Beyond transport, STRA6 functions as a ligand-activated cytokine receptor whose phosphorylation and JAK2/STAT3/STAT5 signaling are triggered specifically by retinol translocation into CRBP-I, making transport and signaling interdependent [#3, #7]. This signaling arm couples circulating RBP4 to insulin action and is suppressed by transthyretin, which blocks holo-RBP association with STRA6 [#4, #6, #9]. STRA6 transcription is directly RA-inducible through a RARE bound by RARγ/RXRα with accompanying p300/H3K27ac changes [#31]. The transporter is essential for ocular vitamin A uptake, visual chromophore/opsin stoichiometry, and outer blood-retinal barrier integrity, and for retinoid supply to brain and testis under dietary limitation [#11, #22, #14, #29]. Loss-of-function STRA6 mutations cause colobomatous microphthalmia, with mislocalizing mutants showing abolished uptake activity [#0, #12]. STRA6-dependent RA signaling additionally drives vascular smooth muscle lineage induction during cardiogenesis via an RARα/RXRα–TBX1 interaction [#21], and its JAK/STAT and ILK/AKT-mTOR outputs promote proliferation, lipogenesis, and survival across multiple cancers [#16, #24, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established STRA6 as a novel hydrophobic membrane protein concentrated at blood-organ barriers and under retinoid-receptor control, framing it as candidate retinoid transport machinery.\",\n      \"evidence\": \"Subtractive hybridization cloning and in situ hybridization in RAR-alpha null mice\",\n      \"pmids\": [\"9203140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical transport activity demonstrated\", \"No direct ligand or partner identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked Stra6 expression to combined Wnt and RA inputs, hinting at transcriptional integration of developmental signals at the STRA6 locus.\",\n      \"evidence\": \"mRNA screening in Wnt-1-stimulated mammary cells and RA-treated colorectal lines\",\n      \"pmids\": [\"11358845\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative expression only; no mechanism of Wnt-RA synergy reconstituted\", \"STRA6 protein function not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Tied STRA6 loss-of-function to human disease and pinpointed functional residues, establishing topology-critical loop and C-terminal signaling motifs.\",\n      \"evidence\": \"Homozygosity mapping, mutational analysis, and topology modeling in patients\",\n      \"pmids\": [\"17273977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of mutant transport defects\", \"SH2/phospho-motif function inferred from sequence, not assayed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that STRA6 mediates bidirectional retinol transfer from RBP4 into cells, enhanced by LRAT, and is required for vitamin A delivery to the developing eye.\",\n      \"evidence\": \"Cell-based retinol transfer assays with LRAT and zebrafish morpholino knockdown\",\n      \"pmids\": [\"18316031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of coupling to intracellular acceptors not yet resolved\", \"Signaling function not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reconstituted STRA6 catalytic logic and showed transport and signaling are interdependent: retinol translocation to CRBP-I, not mere holo-RBP binding, triggers STRA6 phosphorylation and JAK/STAT signaling, and phosphorylation is required for uptake.\",\n      \"evidence\": \"In vitro transport assays with purified components, phosphorylation-deficient mutants, CRBP-I coupling, and TTR competition assays with mouse insulin-resistance models\",\n      \"pmids\": [\"22815070\", \"22665496\", \"22826435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase phosphorylating STRA6 not defined\", \"Structural basis of signaling-competent state unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined STRA6's primary systemic role as coupling circulating holo-RBP to JAK/STAT signaling that suppresses insulin action, with retinol delivery dispensable outside the eye, and showed LRAT-dependent esterification drives the inward transport that activates signaling.\",\n      \"evidence\": \"Stra6-null and LRAT-null mouse models, HPLC retinoid quantification, JAK2/STAT5 assays, glucose tolerance tests; adipocyte differentiation and oncogenic transformation/xenograft assays\",\n      \"pmids\": [\"23839944\", \"24036882\", \"23959802\", \"25237067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why eye retinoid homeostasis is uniquely STRA6-dependent unexplained at this stage\", \"Tissue-specific signaling outputs not fully mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a retinoid-independent, p53-driven pro-apoptotic role for STRA6 acting via mitochondrial depolarization and ROS, broadening its function beyond retinoid transport/signaling.\",\n      \"evidence\": \"DNA damage and p53-dependent transcription assays, ROS and mitochondrial membrane potential measurements with Stra6 knockdown\",\n      \"pmids\": [\"23449393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking STRA6 to mitochondria undefined\", \"How a plasma-membrane transporter drives ROS unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Cemented STRA6 as a bona fide ocular vitamin A transporter and dissected the RA-responsive promoter, showing knockout causes RPE/choroid malformation and cone death, and that an endogenous RARE bound by RARγ/RXRα controls its RA-induced transcription.\",\n      \"evidence\": \"Stra6-knockout mice (HPLC, ERG, histology, rescue), G304K mislocalization assays, zebrafish RA-inhibition models, CRISPR editing of the RARE plus ChIP-seq\",\n      \"pmids\": [\"24852372\", \"21901792\", \"25544292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of STRA6 trafficking to the membrane not detailed\", \"Cone-specific vulnerability mechanism unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural foundation—a homodimer with a lipophilic cleft open to the membrane and tightly bound calmodulin—rationalizing retinol release into the bilayer and RBP docking, and confirmed STRA6's barrier role in eye, brain, and testis.\",\n      \"evidence\": \"3.9 Å cryo-EM of zebrafish STRA6 with RBP-binding residue mapping; Stra6-knockout mice under dietary vitamin A control with multi-tissue retinoid quantification\",\n      \"pmids\": [\"27563101\", \"27189978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational cycle of transport not captured\", \"Functional role of bound calmodulin not established structurally\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended STRA6 signaling to metabolic and oncogenic contexts—β-cell insulin synthesis via JAK2/STAT1/ISL-1, circadian insulin action via REV-ERBα, and colon cancer stem cell maintenance via JAK2/STAT3.\",\n      \"evidence\": \"Islet/INS-1E and RBP4-transgenic models, adipose-specific Stra6 knockout with circadian profiling, colon cancer knockdown with sphere/tumor-initiation assays\",\n      \"pmids\": [\"33199363\", \"28733465\", \"28689994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue specificity of STAT effector usage unexplained\", \"Direct connection of circadian regulation to transport vs signaling unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved how calmodulin engages STRA6—via the BP2 helix in a Ca2+-tunable bilobal manner—and showed STRA6-mediated retinol transfer between hepatic stellate cells and hepatocytes drives fibrogenic lipogenesis.\",\n      \"evidence\": \"NMR/ITC/kinetic analysis of BP2-calmodulin binding; STRA6 knockdown in vitro and in vivo fibrosis models with TIF1γ manipulation\",\n      \"pmids\": [\"34592217\", \"33407858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional effect of Ca2+-calmodulin on transport not directly demonstrated\", \"How interorgan retinol shuttling is triggered in fibrosis unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed STRA6 controls chromophore/opsin stoichiometry in photoreceptors and replenishes retinoids lost to visual-cycle side reactions, explaining the differential rod versus cone dependence on vitamin A.\",\n      \"evidence\": \"Stra6-knockout mice with retinoid quantification, opsin expression/immunolocalization, light-bleaching, and vitamin A rescue\",\n      \"pmids\": [\"34508587\", \"38395306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why cone phenotype resists vitamin A supplementation unexplained\", \"Quantitative flux of byproduct recycling not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established STRA6 as required for vascular smooth muscle lineage induction from human cardiac progenitors, acting through an RARα/RXRα–TBX1 transcriptional interaction.\",\n      \"evidence\": \"STRA6-knockout hESC differentiation, RNA-seq, RARα/RXRα-TBX1 Co-IP, cross-species scRNA-seq\",\n      \"pmids\": [\"36635482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets of the RAR-TBX1 complex not enumerated\", \"Whether transport or signaling activity is the relevant STRA6 function not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded STRA6's disease roles—RBP4/STRA6/JAK2/STAT3-driven muscle atrophy, ILK/AKT-mTOR/SREBP1 signaling in thyroid carcinoma, and m6A-mediated (VIRMA/IGF2BP2) STRA6 mRNA stabilization driving glycolysis in pancreatic cancer.\",\n      \"evidence\": \"C2C12/RBP4-knockout and denervation models; STRA6-ILK Co-IP with knockdown/xenograft; m6A-seq, RIP-seq, and mRNA stability assays in PDAC\",\n      \"pmids\": [\"39031684\", \"36592123\", \"38604311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ILK binding is direct and how it relates to JAK/STAT arm unclear\", \"Generalizability of STRA6-driven lipogenesis across tumor types untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mechanistically linked STRA6 loss to outer blood-retinal barrier failure via impaired retinoid signaling, showing RAR agonist rescues tight-junction gene expression and barrier function.\",\n      \"evidence\": \"Albino Stra6-knockout mice with retinoid quantification, tight-junction protein analysis, ERG, and TTNPB pharmacological rescue\",\n      \"pmids\": [\"41135684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synergy mechanism between melanin and STRA6 not molecularly defined\", \"Which RA-target genes directly maintain junctions not pinpointed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STRA6 mechanically couples retinol translocation to its phosphorylation-dependent switch into a JAK/STAT-competent receptor—and what role bound calmodulin plays in gating transport—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of a signaling-active or substrate-bound human STRA6 conformer\", \"Functional consequence of Ca2+-calmodulin binding on transport untested\", \"Kinase responsible for STRA6 phosphorylation unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 5, 8, 11]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [3, 7, 27]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12, 13, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 5, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [21, 11]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [22, 30, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RBP4\", \"CRBP1\", \"LRAT\", \"TTR\", \"JAK2\", \"CALM1\", \"ILK\", \"IGF2BP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}