{"gene":"NR0B2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"SHP (NR0B2) lacks a conventional DNA-binding domain but contains novel receptor interaction and repressor domains. The central region (amino acids 92–148) mediates interaction with RXRα, thyroid hormone receptor, and retinoic acid receptor; the C-terminal region constitutes an autonomous repressor domain distinct from N-CoR-binding sequences. SHP did not interact with N-CoR in yeast or mammalian two-hybrid systems.","method":"Mammalian two-hybrid, yeast two-hybrid, in vitro binding (deletion and domain mapping), transient transfection repressor assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (yeast two-hybrid, mammalian two-hybrid, in vitro binding, transactivation assays) in a focused mechanistic study","pmids":["9372944"],"is_preprint":false},{"year":1998,"finding":"The SHP gene (Nr0b2) is composed of two exons with a single intron; it is located at human chromosome 1p36.1. Tissue-specific expression is highest in fetal liver, fetal adrenal gland, adult spleen, and adult small intestine, and promoter activity is higher in adrenal-derived cells than HeLa cells.","method":"Genomic library screening, Southern blot, FISH, primer extension, transient transfection promoter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal structural/genomic methods establishing gene organization and tissue expression","pmids":["9603951"],"is_preprint":false},{"year":2001,"finding":"SHP inhibits androgen receptor (AR)-mediated transcription by up to 97%. Interaction requires AR ligand and is mediated by SHP LxxLL (LXXI/LL) motifs binding the AR ligand-binding domain (AR-LBD). SHP also interacts with the AR N-terminal domain (AR-NTD), stabilizing the overall AR–SHP interaction. SHP competes with AR coactivators (FHL2, TIF2) and inhibits both AR-LBD- and AR-NTD-dependent transactivation.","method":"Mammalian two-hybrid, GST pull-down, co-immunoprecipitation, luciferase reporter transactivation assay, competition with coactivators","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal binding and functional assays in a single focused study","pmids":["11735420"],"is_preprint":false},{"year":2002,"finding":"FXR activation induces SHP expression, and increased SHP protein associates with LRH-1 (liver receptor homolog-1), an obligate transcriptional activator of CYP7A1 (cholesterol-7α-hydroxylase), thereby repressing CYP7A1 expression and bile acid synthesis.","method":"Transient transfection reporter assays, co-immunoprecipitation, cited functional studies","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mechanistic model well-established in the field, but this specific abstract is a review summarizing primary data; moderate confidence based on review summary","pmids":["11907135"],"is_preprint":false},{"year":2005,"finding":"SHP represses transcription by recruiting histone deacetylases (HDACs). Two core repressive domains were mapped to amino acids 170–210 and 210–240 of SHP. SHP directly interacts with HDAC1, and SHP, AR, and HDAC1 form a ternary complex. HDAC inhibitor trichostatin A (TSA) reverses SHP-mediated repression of both AR and ERα transactivation.","method":"GST pull-down, co-immunoprecipitation, luciferase reporter assays, TSA pharmacological inhibition, deletion mapping","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, GST pulldown, and functional rescue with pharmacological inhibitor; multiple orthogonal methods","pmids":["15835920"],"is_preprint":false},{"year":2005,"finding":"SHP (NR0B2) acts as an inducible, tissue-specific transcriptional corepressor by directly binding multiple nuclear receptors through its LxxLL-related motifs and suppressing their transactivation. SHP lacks a DNA-binding domain but retains a ligand-binding domain-like region.","method":"Review synthesizing two-hybrid, Co-IP, reporter, and in vivo data from multiple primary studies","journal":"Trends in endocrinology and metabolism: TEM","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — review of replicated findings; mechanism established across multiple labs but this citation is a review","pmids":["16275121"],"is_preprint":false},{"year":2006,"finding":"DAX1 (NR0B1) and SHP (NR0B2) form individual homodimers as well as DAX1–SHP heterodimers in the nucleus of mammalian cells. DAX1 homodimerization involves LXXLL motifs and the AF-2 domain; SHP homodimers dissociate upon heterodimerization with ligand-activated ERα. DAX1–SHP heterodimerization also involves the LXXLL motifs and AF-2 domain of DAX1.","method":"Co-immunoprecipitation, mammalian two-hybrid, subcellular fractionation/localization, BRET assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and two-hybrid in mammalian cells; single lab","pmids":["16709599"],"is_preprint":false},{"year":2008,"finding":"SMILE (SHP-interacting leucine zipper protein) was identified as a new SHP-interacting protein. The N-terminus of SHP and the middle region of SMILE-L mediate their interaction. SMILE isoforms regulate SHP-dependent repression of estrogen receptor transactivation in a cell-type-specific manner; in breast cancer cell lines, SMILE enhances SHP repression of ERα and downregulates ERα-target E2F1 expression.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization (immunofluorescence), siRNA knockdown, adenoviral overexpression, reporter assays, domain-mapping mutagenesis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, Co-IP, co-localization, siRNA, reporter) in a single focused study","pmids":["18657049"],"is_preprint":false},{"year":2009,"finding":"SHP activates miR-206 expression through a cascade dual-inhibitory mechanism: SHP inhibits ERRγ transcriptional activity, leading to decreased YY1 expression; reduced YY1 de-represses AP1 (c-Jun/c-Fos) activity, which then activates the miR-206 promoter. ChIP confirmed physical association of AP1 (c-Jun), YY1, and ERRγ with respective promoters.","method":"Microarray, real-time PCR, RACE, luciferase reporter assay, ChIP, siRNA knockdown, forced expression","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, siRNA, reporter assays, overexpression) establishing cascade in single lab","pmids":["19721712"],"is_preprint":false},{"year":2010,"finding":"SHP (NR0B2) has a cytoplasmic function: it localizes to mitochondria where it binds Bcl-2, disrupts Bcl-2/Bid interaction, and induces cytochrome c release and apoptosis. AHPN promotes SHP translocation from nucleus to mitochondria. SHP activation inhibits peritoneal pancreatic tumor growth.","method":"Co-immunoprecipitation, subcellular fractionation, confocal microscopy, cytochrome c release assay, tumor growth assay, pharmacological induction (AHPN)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, fractionation, and imaging in a single lab; single study","pmids":["20065042"],"is_preprint":false},{"year":2010,"finding":"Two novel missense mutations of SHP (R38H, K170N) impair nuclear translocation. K170N makes SHP more susceptible to ubiquitin-mediated degradation, blocks SHP acetylation, and abolishes repressive activity on ERRγ and HNF4α but not LRH-1. G171A stabilizes nuclear receptor boxes. K170N impairs recruitment of SHP, HNF4α, HDAC1, and HDAC3 to the apoCIII promoter. Molecular dynamics simulations show G171A stabilizes and K170N destabilizes structural elements of the receptor.","method":"Mutant expression, nuclear translocation assay, ubiquitination assay, acetylation assay, reporter assays, ChIP, molecular dynamics simulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ChIP, reporter, structural simulation, PTM assays) establishing functional consequences of specific residues","pmids":["20516075"],"is_preprint":false},{"year":2010,"finding":"FXR activates SHP (Nr0b2) transcription through two FXR response elements (FXRREs): one in the proximal promoter and a novel one in the 3'-enhancer region. These two FXRREs interact via head-to-tail chromatin looping to increase SHP transcription efficiency.","method":"ChIP-seq, ChIP-qPCR, luciferase reporter assay, site-directed mutagenesis, chromatin conformation capture (3C) assay","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct demonstration of chromatin looping by 3C, supported by ChIP-seq and mutagenesis","pmids":["20444884"],"is_preprint":false},{"year":2011,"finding":"SHP represses Dnmt1 expression by inhibiting ERRγ transactivation; ERRγ binds directly to ERE1/ERE2 response elements in the Dnmt1 promoter and activates transcription, while SHP diminishes ERRγ recruitment and shifts local chromatin to an inactive conformation. SHP-knockout mice show increased Dnmt1 expression; SHP-transgenic mice show decreased Dnmt1.","method":"Reporter assays, ChIP, co-immunoprecipitation, SHP-KO and SHP-transgenic mouse models, Western blot","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, Co-IP, reporter, and in vivo genetic models provide convergent evidence","pmids":["21459093"],"is_preprint":false},{"year":2012,"finding":"SHP inhibits zinc-induced Dnmt1 expression by antagonizing MTF-1 (metal-responsive transcription factor-1). Zinc induces MTF-1 occupancy on the Dnmt1 promoter; SHP represses MTF-1 expression and abolishes zinc-mediated chromatin changes at the Dnmt1 promoter. SHP-KO mice have increased Dnmt1; SHP-transgenic mice have decreased Dnmt1.","method":"Reporter assays, ChIP, co-immunoprecipitation, SHP-KO and SHP-transgenic mice, Western blot","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, Co-IP, reporter, in vivo KO/TG models)","pmids":["22362755"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of SHP in complex with EID1 reveals an unexpected binding site at the N-terminus of the receptor (mimicking helix H1 of the nuclear receptor LBD), distinct from the classical C-terminal H12 cofactor-binding site. Mutations at the SHP–EID1 interface diminish their interaction and reduce SHP repressor activity.","method":"X-ray crystallography, mutagenesis, in vitro binding, reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure solved and validated by mutagenesis and functional assays","pmids":["24379397"],"is_preprint":false},{"year":2004,"finding":"G93D missense mutation of SHP (NR0B2) shows reduced in vitro inhibition of HNF-4α transactivation of the HNF-1α promoter when expressed in MIN6-m9 and HepG2 cells, demonstrating that the G93 residue contributes to SHP repressor function.","method":"SSCP/heteroduplex mutation analysis, transient transfection reporter assay in MIN6-m9 and HepG2 cells","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay in two cell lines, single lab","pmids":["15459958"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the AR ligand-binding domain in complex with a 14-mer peptide from SHP NR Box 2 (LKKIL motif) reveals that SHP binds the same hydrophobic groove on AR used by coactivators. Only NR Box 2 of SHP formed a crystal complex with AR-LBD under the conditions tested, and SHP inhibits AR by competing with coactivators at this site.","method":"X-ray crystallography (AR-LBD/SHP peptide co-crystal), structural comparison with coactivator-bound AR complexes","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with defined binding mode; single study/lab","pmids":["18007036"],"is_preprint":false},{"year":2015,"finding":"SHP interacts with FOXA1 to oscillatorily regulate homocysteine metabolism genes (Bhmt, cystathionine γ-lyase). SHP inhibits FOXA1-mediated transcriptional activation of Bhmt and cystathionine γ-lyase, controlling oscillatory production of S-adenosylmethionine, betaine, and related metabolites. SHP-null mice have altered circadian timing of homocysteine metabolism gene expression and are protected from ethanol- and homocysteine-induced hyperhomocysteinemia.","method":"RNA-seq, metabolomics, ChIP, immunoblot, SHP-null mouse model, gene expression (qPCR), 24-h light-dark cycle sampling","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, SHP-KO mice, and metabolomics provide multiple orthogonal lines of evidence for this interaction and pathway","pmids":["25701738"],"is_preprint":false},{"year":2018,"finding":"AhR activates Pemt and Gnmt (one-carbon cycle genes regulating PC/SAM levels) in the early fed state; SHP, activated by FGF15 signaling in the late fed state, blocks this AhR-mediated induction. SHP-null mice fail to suppress AhR-driven Pemt/Gnmt expression, altering PC and SAM levels. Adenoviral AhR in obese mice exacerbates steatosis, and co-expression of SHP blunts this effect.","method":"SHP-null mouse model, adenoviral overexpression, ChIP, reporter assays, metabolomic analysis, immunoblot","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model, adenoviral rescue, ChIP, and metabolomics provide convergent mechanistic evidence","pmids":["29416063"],"is_preprint":false},{"year":2014,"finding":"NF-κB p65 recruits SHP (NR0B2) to the PDCD5 gene promoter; a SHP/NF-κB p65 complex is found on the PDCD5 gene, and 3-Cl-AHPC-mediated apoptosis increases SHP mRNA/protein and the SHP/p65 interaction. PDCD5 induction triggers apoptosis via increased Bax and cytochrome c release.","method":"ChIP-on-chip, ChIP, co-immunoprecipitation, reporter assay, siRNA knockdown, overexpression, Western blot","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP identify the complex; single lab","pmids":["24343129"],"is_preprint":false},{"year":2014,"finding":"LH/CG represses Nr0b2 (SHP) expression in testicular Leydig cells through the protein kinase A–AMP protein kinase (PKA–AMPK) pathway. NR0B2 mediates the repression of testosterone synthesis and subsequent germ cell apoptosis induced by anti-GnRH compounds, establishing a functional link between the hypothalamo-pituitary axis and NR0B2 in testicular androgen metabolism.","method":"Transgenic NR0B2-null mouse model, pharmacological pathway inhibitors (PKA, AMPK), hormone treatment, testosterone measurement, TUNEL assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model with defined hormonal pathway; single lab","pmids":["25426871"],"is_preprint":false}],"current_model":"NR0B2/SHP is an atypical nuclear receptor that lacks a DNA-binding domain but contains LxxLL-like motifs and a ligand-binding domain-like region; it functions as an inducible transcriptional corepressor by directly binding numerous nuclear receptors (including RXRα, AR, ERα, LRH-1, HNF4α, ERRγ) and recruiting HDAC1/3 complexes, and by physically interacting with non-receptor partners (EID1, SMILE, FOXA1, MTF-1, NF-κB p65, AhR) to suppress target gene transcription—including bile acid (CYP7A1), lipid (SREBP1c, Dnmt1, Pemt, Gnmt), and steroid hormone pathway genes—while also possessing a cytoplasmic apoptotic function through mitochondrial translocation and Bcl-2 binding."},"narrative":{"mechanistic_narrative":"NR0B2/SHP is an atypical, inducible nuclear receptor that functions principally as a transcriptional corepressor, lacking a conventional DNA-binding domain while retaining a receptor-interaction region and an autonomous C-terminal repressor domain [PMID:9372944]. It silences target genes by directly binding the ligand-binding domains of partner nuclear receptors through LxxLL-related motifs (NR boxes) that occupy the same hydrophobic coactivator groove, thereby competing out coactivators—demonstrated structurally for androgen receptor, where SHP NR Box 2 docks into the AR-LBD groove used by FHL2 and TIF2 [PMID:11735420, PMID:18007036]. SHP enforces repression by recruiting histone deacetylases, forming ternary complexes with target receptors and HDAC1/HDAC3 that can be reversed pharmacologically with the HDAC inhibitor TSA [PMID:15835920, PMID:20516075]. Beyond classical receptor binding, SHP engages non-receptor partners: a crystal structure with EID1 revealed a second, N-terminal interaction surface mimicking helix H1 of the nuclear receptor LBD, distinct from the C-terminal cofactor site [PMID:24379397], and SHP also partners with SMILE and FOXA1 to modulate repression in a cell-type- and tissue-specific manner [PMID:18657049, PMID:25701738]. As an FGF/FXR-inducible factor—its own transcription driven by FXR through chromatin-looping FXR response elements [PMID:20444884]—SHP integrates into bile acid and lipid metabolic control, repressing LRH-1-driven CYP7A1 and bile acid synthesis [PMID:11907135] and suppressing one-carbon and lipid genes (Dnmt1, Pemt, Gnmt) by antagonizing ERRγ, MTF-1, and AhR [PMID:21459093, PMID:22362755, PMID:29416063]. SHP additionally possesses a cytoplasmic apoptotic function: upon pharmacological induction it translocates to mitochondria, binds Bcl-2, disrupts Bcl-2/Bid interaction, and triggers cytochrome c release [PMID:20065042]. Missense mutations (G93D, R38H, K170N) that impair repressor activity or nuclear translocation establish specific residues required for SHP function [PMID:20516075, PMID:15459958].","teleology":[{"year":1997,"claim":"Established SHP as a structurally unconventional nuclear receptor—lacking a DNA-binding domain but carrying distinct receptor-interaction and repressor modules—reframing how it could act on transcription.","evidence":"Domain mapping by yeast/mammalian two-hybrid and in vitro binding with transactivation assays","pmids":["9372944"],"confidence":"High","gaps":["Mechanism of repression (cofactor recruitment) not yet defined","Physiological target genes unidentified"]},{"year":1998,"claim":"Defined the gene's two-exon structure, chromosomal location, and tissue-restricted expression, anchoring SHP in liver, adrenal, and intestinal biology.","evidence":"Genomic library screening, FISH, primer extension, promoter assays","pmids":["9603951"],"confidence":"High","gaps":["Does not establish the upstream signals controlling tissue-specific induction"]},{"year":2001,"claim":"Showed SHP represses androgen receptor by competing with coactivators via LxxLL motifs, extending its corepressor role to steroid hormone signaling.","evidence":"Two-hybrid, GST pull-down, Co-IP, reporter and coactivator competition assays","pmids":["11735420"],"confidence":"High","gaps":["Structural basis of competition not yet resolved","Did not address downstream effector recruitment"]},{"year":2002,"claim":"Placed SHP in the FXR-bile acid feedback loop, where it represses LRH-1 to shut down CYP7A1 and bile acid synthesis.","evidence":"Reporter assays and Co-IP summarized in a review of primary data","pmids":["11907135"],"confidence":"Medium","gaps":["Summarized from review rather than primary data","Chromatin-level mechanism on CYP7A1 not detailed here"]},{"year":2004,"claim":"Demonstrated that a single residue (G93) is required for SHP repression of HNF-4α, linking specific structure to repressor output.","evidence":"Mutation analysis and reporter assays in MIN6-m9 and HepG2 cells","pmids":["15459958"],"confidence":"Medium","gaps":["Functional assay in cell lines only; in vivo consequence not tested","Single lab"]},{"year":2005,"claim":"Identified HDAC recruitment as the effector mechanism of SHP repression, mapping repressive subdomains and showing AR/SHP/HDAC1 ternary complex formation reversible by TSA.","evidence":"GST pull-down, Co-IP, reporter assays, TSA inhibition, deletion mapping","pmids":["15835920"],"confidence":"High","gaps":["Whether HDAC recruitment is universal across all SHP target receptors not established","Additional corepressor partners not excluded"]},{"year":2006,"claim":"Showed SHP can homodimerize and heterodimerize with DAX1, with ligand-activated ERα dissociating SHP homodimers, adding a dimerization layer to its regulation.","evidence":"Co-IP, mammalian two-hybrid, fractionation, BRET in mammalian cells","pmids":["16709599"],"confidence":"Medium","gaps":["Functional consequence of homo- vs heterodimer not resolved","Single lab"]},{"year":2008,"claim":"Identified SMILE as a SHP partner that tunes SHP repression of ERα in a cell-type-specific manner, expanding the non-receptor partner repertoire.","evidence":"Yeast two-hybrid, Co-IP, co-localization, siRNA, reporter, domain mapping","pmids":["18657049"],"confidence":"High","gaps":["Structural basis of SHP-SMILE interaction unresolved","In vivo relevance not tested"]},{"year":2009,"claim":"Revealed that SHP can indirectly activate gene expression through a dual-inhibitory ERRγ→YY1→AP1 cascade driving miR-206, showing its repression can yield net activation downstream.","evidence":"Microarray, qPCR, RACE, reporter, ChIP, siLP, forced expression","pmids":["19721712"],"confidence":"High","gaps":["Physiological context of miR-206 regulation by SHP not defined"]},{"year":2010,"claim":"Established a cytoplasmic, mitochondrial apoptotic function for SHP via Bcl-2 binding and cytochrome c release, distinct from its nuclear corepressor role.","evidence":"Co-IP, fractionation, confocal imaging, cytochrome c release, tumor growth assays with AHPN induction","pmids":["20065042"],"confidence":"Medium","gaps":["Signal triggering nuclear-to-mitochondrial translocation incompletely defined","Single lab"]},{"year":2010,"claim":"Mapped how disease-associated residues (R38H, K170N, G171A) control SHP nuclear translocation, acetylation, stability, and target-selective repression, connecting residue chemistry to function.","evidence":"Mutant expression, translocation/ubiquitination/acetylation assays, ChIP, reporter, molecular dynamics","pmids":["20516075"],"confidence":"High","gaps":["Why repression of LRH-1 is spared by K170N not mechanistically explained"]},{"year":2010,"claim":"Defined how SHP's own transcription is amplified by FXR through two response elements brought together by chromatin looping, explaining its rapid inducibility.","evidence":"ChIP-seq, ChIP-qPCR, reporter, mutagenesis, 3C chromatin conformation capture","pmids":["20444884"],"confidence":"High","gaps":["Looping factors mediating the FXRRE interaction not identified"]},{"year":2011,"claim":"Showed SHP controls DNA methylation machinery by repressing Dnmt1 through ERRγ antagonism, confirmed in KO and transgenic mice.","evidence":"Reporter, ChIP, Co-IP, SHP-KO and SHP-transgenic mice, Western blot","pmids":["21459093"],"confidence":"High","gaps":["Downstream methylation targets affected not catalogued"]},{"year":2012,"claim":"Extended SHP's Dnmt1 control to antagonism of the metal-responsive factor MTF-1, showing it integrates zinc signaling into epigenetic regulation.","evidence":"Reporter, ChIP, Co-IP, SHP-KO and transgenic mice, Western blot","pmids":["22362755"],"confidence":"High","gaps":["Direct vs indirect repression of MTF-1 not fully separated"]},{"year":2013,"claim":"Solved a crystal structure of SHP bound to EID1, revealing a non-canonical N-terminal interaction surface distinct from the classical H12 cofactor site.","evidence":"X-ray crystallography, mutagenesis, in vitro binding, reporter assay","pmids":["24379397"],"confidence":"High","gaps":["Whether other partners use this same N-terminal site not established"]},{"year":2014,"claim":"Provided a structural view of how SHP NR Box 2 occupies the AR coactivator groove, explaining coactivator competition at atomic resolution.","evidence":"X-ray crystallography of AR-LBD/SHP peptide complex, structural comparison","pmids":["18007036"],"confidence":"High","gaps":["Contribution of NR Box 1 and N-terminal contacts to full-length binding not captured in peptide co-crystal"]},{"year":2014,"claim":"Linked SHP to NF-κB-driven apoptosis, showing p65 recruits SHP to the PDCD5 promoter to promote a pro-apoptotic program.","evidence":"ChIP-on-chip, ChIP, Co-IP, reporter, siRNA, overexpression, Western blot","pmids":["24343129"],"confidence":"Medium","gaps":["Whether SHP activates or represses PDCD5 in this context not fully clarified","Single lab"]},{"year":2014,"claim":"Placed Nr0b2 under hypothalamo-pituitary control via LH/CG-PKA-AMPK signaling in Leydig cells, mediating testosterone repression and germ cell apoptosis.","evidence":"NR0B2-null mice, PKA/AMPK inhibitors, hormone treatment, testosterone measurement, TUNEL","pmids":["25426871"],"confidence":"Medium","gaps":["Direct SHP target genes in steroidogenesis not mapped","Single lab"]},{"year":2015,"claim":"Showed SHP interacts with FOXA1 to impose circadian, oscillatory control over homocysteine metabolism genes, protecting against hyperhomocysteinemia.","evidence":"RNA-seq, metabolomics, ChIP, immunoblot, SHP-null mice, time-course sampling","pmids":["25701738"],"confidence":"High","gaps":["Mechanism coupling SHP to circadian clock inputs not detailed"]},{"year":2018,"claim":"Demonstrated SHP, induced by FGF15 in the late fed state, antagonizes AhR-driven Pemt/Gnmt one-carbon gene induction, positioning SHP as a temporal switch in hepatic lipid/methyl metabolism.","evidence":"SHP-null mice, adenoviral overexpression/rescue, ChIP, reporter, metabolomics","pmids":["29416063"],"confidence":"High","gaps":["Direct SHP-AhR physical contact vs competition for promoter not fully resolved"]},{"year":null,"claim":"How SHP's nuclear corepressor activity and its cytoplasmic mitochondrial pro-apoptotic function are coordinated, and what signals govern its subcellular partitioning, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Translocation signal and trigger not defined","Integration of metabolic, apoptotic, and circadian roles within single cells unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4,16]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,12,13,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,8,11]}],"complexes":[],"partners":["RXRA","AR","LRH-1","HNF4A","ERRG","HDAC1","EID1","FOXA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15466","full_name":"Nuclear receptor subfamily 0 group B member 2","aliases":["Orphan nuclear receptor SHP","Small heterodimer partner"],"length_aa":257,"mass_kda":28.1,"function":"Transcriptional regulator that acts as a negative regulator of receptor-dependent signaling pathways (PubMed:22504882). Specifically inhibits transactivation of the nuclear receptor with which it interacts (PubMed:22504882). Inhibits transcriptional activity of NEUROD1 on E-box-containing promoter by interfering with the coactivation function of the p300/CBP-mediated transcription complex for NEUROD1 (PubMed:14752053). Essential component of the liver circadian clock which via its interaction with NR1D1 and RORG regulates NPAS2-mediated hepatic lipid metabolism (By similarity). Regulates the circadian expression of cytochrome P450 (CYP) enzymes (By similarity). Represses: NR5A2 and HNF4A to down-regulate CYP2C38, NFLI3 to up-regulate CYP2A5, BHLHE41/HNF1A axis to up-regulate CYP1A2, CYP2E1 and CYP3A11, and NR1D1 to up-regulate CYP2B10, CYP4A10 and CYP4A14 (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15466/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR0B2","classification":"Not Classified","n_dependent_lines":49,"n_total_lines":1208,"dependency_fraction":0.04056291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR0B2","total_profiled":1310},"omim":[{"mim_id":"611135","title":"KLOTHO, BETA; KLB","url":"https://www.omim.org/entry/611135"},{"mim_id":"604630","title":"NUCLEAR RECEPTOR SUBFAMILY 0, GROUP B, MEMBER 2; NR0B2","url":"https://www.omim.org/entry/604630"},{"mim_id":"604453","title":"NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 2; NR5A2","url":"https://www.omim.org/entry/604453"},{"mim_id":"603826","title":"NUCLEAR RECEPTOR SUBFAMILY 1, GROUP H, MEMBER 4; NR1H4","url":"https://www.omim.org/entry/603826"},{"mim_id":"602397","title":"ATPase, CLASS I, TYPE 8B, MEMBER 1; ATP8B1","url":"https://www.omim.org/entry/602397"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":72.2},{"tissue":"liver","ntpm":140.3}],"url":"https://www.proteinatlas.org/search/NR0B2"},"hgnc":{"alias_symbol":["SHP"],"prev_symbol":[]},"alphafold":{"accession":"Q15466","domains":[{"cath_id":"1.10.565.10","chopping":"40-113_140-256","consensus_level":"medium","plddt":92.4177,"start":40,"end":256}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15466","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15466-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15466-F1-predicted_aligned_error_v6.png","plddt_mean":81.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR0B2","jax_strain_url":"https://www.jax.org/strain/search?query=NR0B2"},"sequence":{"accession":"Q15466","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15466.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15466/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15466"}},"corpus_meta":[{"pmid":"12826400","id":"PMC_12826400","title":"The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling.","date":"2003","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12826400","citation_count":1015,"is_preprint":false},{"pmid":"9244303","id":"PMC_9244303","title":"Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9244303","citation_count":380,"is_preprint":false},{"pmid":"9694867","id":"PMC_9694867","title":"Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9694867","citation_count":343,"is_preprint":false},{"pmid":"19881493","id":"PMC_19881493","title":"Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy.","date":"2009","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19881493","citation_count":326,"is_preprint":false},{"pmid":"19290938","id":"PMC_19290938","title":"SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels.","date":"2009","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/19290938","citation_count":304,"is_preprint":false},{"pmid":"10579910","id":"PMC_10579910","title":"Shp-2 tyrosine phosphatase: signaling one cell or many.","date":"1999","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/10579910","citation_count":245,"is_preprint":false},{"pmid":"12657462","id":"PMC_12657462","title":"The function of the protein tyrosine phosphatase SHP-1 in cancer.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12657462","citation_count":237,"is_preprint":false},{"pmid":"17157040","id":"PMC_17157040","title":"SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production.","date":"2006","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17157040","citation_count":207,"is_preprint":false},{"pmid":"17647198","id":"PMC_17647198","title":"The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury.","date":"2007","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/17647198","citation_count":203,"is_preprint":false},{"pmid":"20970497","id":"PMC_20970497","title":"Role of nuclear receptor SHP in metabolism and cancer.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20970497","citation_count":197,"is_preprint":false},{"pmid":"10206955","id":"PMC_10206955","title":"The myeloid-specific sialic acid-binding receptor, CD33, associates with the protein-tyrosine phosphatases, SHP-1 and SHP-2.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10206955","citation_count":153,"is_preprint":false},{"pmid":"32184441","id":"PMC_32184441","title":"Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/32184441","citation_count":146,"is_preprint":false},{"pmid":"16084691","id":"PMC_16084691","title":"A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail.","date":"2005","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/16084691","citation_count":144,"is_preprint":false},{"pmid":"9261115","id":"PMC_9261115","title":"Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9261115","citation_count":141,"is_preprint":false},{"pmid":"11191350","id":"PMC_11191350","title":"The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions.","date":"2000","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11191350","citation_count":138,"is_preprint":false},{"pmid":"11907135","id":"PMC_11907135","title":"Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP.","date":"2002","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/11907135","citation_count":130,"is_preprint":false},{"pmid":"17442246","id":"PMC_17442246","title":"Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/17442246","citation_count":128,"is_preprint":false},{"pmid":"24333736","id":"PMC_24333736","title":"Capillarisin inhibits constitutive and inducible STAT3 activation through induction of SHP-1 and SHP-2 tyrosine phosphatases.","date":"2013","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/24333736","citation_count":124,"is_preprint":false},{"pmid":"10488096","id":"PMC_10488096","title":"SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10488096","citation_count":122,"is_preprint":false},{"pmid":"16275121","id":"PMC_16275121","title":"Transcriptional corepression by SHP: molecular mechanisms and physiological consequences.","date":"2005","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/16275121","citation_count":118,"is_preprint":false},{"pmid":"9372944","id":"PMC_9372944","title":"Novel receptor interaction and repression domains in the orphan receptor SHP.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9372944","citation_count":115,"is_preprint":false},{"pmid":"16617349","id":"PMC_16617349","title":"The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis.","date":"2006","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16617349","citation_count":112,"is_preprint":false},{"pmid":"12421673","id":"PMC_12421673","title":"Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response.","date":"2002","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12421673","citation_count":109,"is_preprint":false},{"pmid":"23391724","id":"PMC_23391724","title":"SHP-1 phosphatase activity counteracts increased T cell receptor affinity.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23391724","citation_count":104,"is_preprint":false},{"pmid":"10781410","id":"PMC_10781410","title":"Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction.","date":"2000","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10781410","citation_count":103,"is_preprint":false},{"pmid":"9418864","id":"PMC_9418864","title":"Structural determinants of SHP-2 function and specificity in Xenopus mesoderm induction.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9418864","citation_count":99,"is_preprint":false},{"pmid":"11159516","id":"PMC_11159516","title":"Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11159516","citation_count":97,"is_preprint":false},{"pmid":"10506221","id":"PMC_10506221","title":"Regulation of acidification and apoptosis by SHP-1 and Bcl-2.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10506221","citation_count":95,"is_preprint":false},{"pmid":"15933714","id":"PMC_15933714","title":"Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15933714","citation_count":95,"is_preprint":false},{"pmid":"12615921","id":"PMC_12615921","title":"Identification of Shp-2 as a Stat5A phosphatase.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12615921","citation_count":94,"is_preprint":false},{"pmid":"14676626","id":"PMC_14676626","title":"SHP-2 and myeloid malignancies.","date":"2004","source":"Current opinion in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/14676626","citation_count":93,"is_preprint":false},{"pmid":"9814969","id":"PMC_9814969","title":"Regulation of angiotensin II-induced JAK2 tyrosine phosphorylation: roles of SHP-1 and SHP-2.","date":"1998","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9814969","citation_count":93,"is_preprint":false},{"pmid":"9603951","id":"PMC_9603951","title":"Structure and expression of the orphan nuclear receptor SHP gene.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9603951","citation_count":90,"is_preprint":false},{"pmid":"21291263","id":"PMC_21291263","title":"Substrate specificity of protein tyrosine phosphatases 1B, RPTPα, SHP-1, and SHP-2.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21291263","citation_count":87,"is_preprint":false},{"pmid":"20065042","id":"PMC_20065042","title":"Nuclear receptor SHP, a death receptor that targets mitochondria, induces apoptosis and inhibits tumor growth.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20065042","citation_count":85,"is_preprint":false},{"pmid":"12370245","id":"PMC_12370245","title":"Gab1 and SHP-2 promote Ras/MAPK regulation of epidermal growth and differentiation.","date":"2002","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12370245","citation_count":75,"is_preprint":false},{"pmid":"21393858","id":"PMC_21393858","title":"SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans.","date":"2011","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/21393858","citation_count":75,"is_preprint":false},{"pmid":"36581713","id":"PMC_36581713","title":"SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses.","date":"2022","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36581713","citation_count":74,"is_preprint":false},{"pmid":"29776962","id":"PMC_29776962","title":"SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29776962","citation_count":73,"is_preprint":false},{"pmid":"11735420","id":"PMC_11735420","title":"Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11735420","citation_count":70,"is_preprint":false},{"pmid":"9348315","id":"PMC_9348315","title":"Downregulated expression of SHP-1 in Burkitt lymphomas and germinal center B lymphocytes.","date":"1997","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9348315","citation_count":62,"is_preprint":false},{"pmid":"21291405","id":"PMC_21291405","title":"SHP-1 in cell-cycle regulation.","date":"2011","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21291405","citation_count":61,"is_preprint":false},{"pmid":"16041024","id":"PMC_16041024","title":"Heme transfer from streptococcal cell surface protein Shp to HtsA of transporter HtsABC.","date":"2005","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/16041024","citation_count":60,"is_preprint":false},{"pmid":"12176909","id":"PMC_12176909","title":"SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12176909","citation_count":59,"is_preprint":false},{"pmid":"10835420","id":"PMC_10835420","title":"The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10835420","citation_count":58,"is_preprint":false},{"pmid":"16702225","id":"PMC_16702225","title":"Sequence specificity of SHP-1 and SHP-2 Src homology 2 domains. Critical roles of residues beyond the pY+3 position.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16702225","citation_count":56,"is_preprint":false},{"pmid":"29416063","id":"PMC_29416063","title":"AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29416063","citation_count":53,"is_preprint":false},{"pmid":"29514104","id":"PMC_29514104","title":"Large-Scale Phosphoproteomics Reveals Shp-2 Phosphatase-Dependent Regulators of Pdgf Receptor Signaling.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29514104","citation_count":53,"is_preprint":false},{"pmid":"29669741","id":"PMC_29669741","title":"SHP-1 regulates hematopoietic stem cell quiescence by coordinating TGF-β signaling.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29669741","citation_count":51,"is_preprint":false},{"pmid":"25187664","id":"PMC_25187664","title":"SHP-1 plays a crucial role in CD40 signaling reciprocity.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25187664","citation_count":51,"is_preprint":false},{"pmid":"28594363","id":"PMC_28594363","title":"Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28594363","citation_count":48,"is_preprint":false},{"pmid":"25701738","id":"PMC_25701738","title":"Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice.","date":"2015","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25701738","citation_count":48,"is_preprint":false},{"pmid":"15835920","id":"PMC_15835920","title":"SHP represses transcriptional activity via recruitment of histone deacetylases.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15835920","citation_count":47,"is_preprint":false},{"pmid":"31708921","id":"PMC_31708921","title":"SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31708921","citation_count":46,"is_preprint":false},{"pmid":"25071018","id":"PMC_25071018","title":"SHP-1 is a target of regorafenib in colorectal cancer.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25071018","citation_count":46,"is_preprint":false},{"pmid":"32210977","id":"PMC_32210977","title":"Nrf2-SHP Cascade-Mediated STAT3 Inactivation Contributes to AMPK-Driven Protection Against Endotoxic Inflammation.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32210977","citation_count":44,"is_preprint":false},{"pmid":"19721712","id":"PMC_19721712","title":"Nuclear receptor SHP activates miR-206 expression via a cascade dual inhibitory mechanism.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19721712","citation_count":44,"is_preprint":false},{"pmid":"27068940","id":"PMC_27068940","title":"SHP-1: the next checkpoint target for cancer immunotherapy?","date":"2016","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/27068940","citation_count":43,"is_preprint":false},{"pmid":"18657049","id":"PMC_18657049","title":"SMILE, a new orphan nuclear receptor SHP-interacting protein, regulates SHP-repressed estrogen receptor transactivation.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18657049","citation_count":43,"is_preprint":false},{"pmid":"20516075","id":"PMC_20516075","title":"Novel polymorphisms of nuclear receptor SHP associated with functional and structural changes.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20516075","citation_count":42,"is_preprint":false},{"pmid":"22415018","id":"PMC_22415018","title":"Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1.","date":"2012","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/22415018","citation_count":39,"is_preprint":false},{"pmid":"20444884","id":"PMC_20444884","title":"Farnesoid X receptor activation mediates head-to-tail chromatin looping in the Nr0b2 gene encoding small heterodimer partner.","date":"2010","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/20444884","citation_count":37,"is_preprint":false},{"pmid":"19915046","id":"PMC_19915046","title":"SHP-2 expression negatively regulates NK cell function.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19915046","citation_count":37,"is_preprint":false},{"pmid":"20130595","id":"PMC_20130595","title":"Deficient SOCS3 and SHP-1 expression in psoriatic T cells.","date":"2010","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20130595","citation_count":37,"is_preprint":false},{"pmid":"15574429","id":"PMC_15574429","title":"FLT3/ITD mutation signaling includes suppression of SHP-1.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15574429","citation_count":37,"is_preprint":false},{"pmid":"10098842","id":"PMC_10098842","title":"Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins.","date":"1999","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10098842","citation_count":37,"is_preprint":false},{"pmid":"34014331","id":"PMC_34014331","title":"Luteolin alleviates ulcerative colitis through SHP-1/STAT3 pathway.","date":"2021","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/34014331","citation_count":36,"is_preprint":false},{"pmid":"37263401","id":"PMC_37263401","title":"Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway.","date":"2023","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37263401","citation_count":36,"is_preprint":false},{"pmid":"23531619","id":"PMC_23531619","title":"Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes.","date":"2013","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23531619","citation_count":33,"is_preprint":false},{"pmid":"24439672","id":"PMC_24439672","title":"Expression and clinical significance of tyrosine phosphatase SHP-2 in colon cancer.","date":"2013","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/24439672","citation_count":32,"is_preprint":false},{"pmid":"37304233","id":"PMC_37304233","title":"Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals.","date":"2023","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/37304233","citation_count":32,"is_preprint":false},{"pmid":"21459093","id":"PMC_21459093","title":"Nuclear receptor SHP inhibition of Dnmt1 expression via ERRγ.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21459093","citation_count":32,"is_preprint":false},{"pmid":"16223786","id":"PMC_16223786","title":"RNA interference targeting SHP-1 attenuates myocardial infarction in rats.","date":"2005","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/16223786","citation_count":32,"is_preprint":false},{"pmid":"20124506","id":"PMC_20124506","title":"Overexpression of nuclear receptor SHP in adipose tissues affects diet-induced obesity and adaptive thermogenesis.","date":"2010","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/20124506","citation_count":32,"is_preprint":false},{"pmid":"31561841","id":"PMC_31561841","title":"Regulation of peripheral and central immunity: Understanding the role of Src homology 2 domain-containing tyrosine phosphatases, SHP-1 & SHP-2.","date":"2019","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31561841","citation_count":31,"is_preprint":false},{"pmid":"31232447","id":"PMC_31232447","title":"Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2-mediated signaling.","date":"2019","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31232447","citation_count":31,"is_preprint":false},{"pmid":"14563118","id":"PMC_14563118","title":"SHP-1: a regulator of neutrophil apoptosis.","date":"2003","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14563118","citation_count":30,"is_preprint":false},{"pmid":"17928416","id":"PMC_17928416","title":"SHP-2 is required for the maintenance of cardiac progenitors.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17928416","citation_count":30,"is_preprint":false},{"pmid":"34752140","id":"PMC_34752140","title":"Dynamic variability in SHP-1 abundance determines natural killer cell responsiveness.","date":"2021","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/34752140","citation_count":29,"is_preprint":false},{"pmid":"27670070","id":"PMC_27670070","title":"Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27670070","citation_count":29,"is_preprint":false},{"pmid":"22362755","id":"PMC_22362755","title":"Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22362755","citation_count":29,"is_preprint":false},{"pmid":"21550402","id":"PMC_21550402","title":"Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease.","date":"2011","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21550402","citation_count":28,"is_preprint":false},{"pmid":"16709599","id":"PMC_16709599","title":"Dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1) (NR0B1) and small heterodimer partner (SHP) (NR0B2) form homodimers individually, as well as DAX1-SHP heterodimers.","date":"2006","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/16709599","citation_count":28,"is_preprint":false},{"pmid":"22438258","id":"PMC_22438258","title":"The tyrosine phosphatase SHP-1 dampens murine Th17 development.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22438258","citation_count":27,"is_preprint":false},{"pmid":"35034964","id":"PMC_35034964","title":"SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35034964","citation_count":26,"is_preprint":false},{"pmid":"12769687","id":"PMC_12769687","title":"Gab1, SHP-2 and other novel regulators of Ras: targets for anticancer drug discovery?","date":"2003","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/12769687","citation_count":26,"is_preprint":false},{"pmid":"34460026","id":"PMC_34460026","title":"SHP-1/STAT3 Interaction Is Related to Luteolin-Induced Myocardial Ischemia Protection.","date":"2021","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/34460026","citation_count":26,"is_preprint":false},{"pmid":"24379397","id":"PMC_24379397","title":"Structural insights into gene repression by the orphan nuclear receptor SHP.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24379397","citation_count":26,"is_preprint":false},{"pmid":"9048211","id":"PMC_9048211","title":"Regulation of cell signaling by the protein tyrosine phosphatases, CD45 and SHP-1.","date":"1997","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/9048211","citation_count":25,"is_preprint":false},{"pmid":"24343129","id":"PMC_24343129","title":"NF-κB p65 recruited SHP regulates PDCD5-mediated apoptosis in cancer cells.","date":"2014","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/24343129","citation_count":24,"is_preprint":false},{"pmid":"36638873","id":"PMC_36638873","title":"Epiberberine regulates lipid synthesis through SHP (NR0B2) to improve non-alcoholic steatohepatitis.","date":"2023","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/36638873","citation_count":23,"is_preprint":false},{"pmid":"27812544","id":"PMC_27812544","title":"Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity.","date":"2016","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/27812544","citation_count":23,"is_preprint":false},{"pmid":"29518948","id":"PMC_29518948","title":"ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion.","date":"2018","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/29518948","citation_count":23,"is_preprint":false},{"pmid":"11493654","id":"PMC_11493654","title":"SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11493654","citation_count":23,"is_preprint":false},{"pmid":"15459958","id":"PMC_15459958","title":"Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity.","date":"2004","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/15459958","citation_count":22,"is_preprint":false},{"pmid":"32586377","id":"PMC_32586377","title":"Regulation of autoimmune arthritis by the SHP-1 tyrosine phosphatase.","date":"2020","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32586377","citation_count":22,"is_preprint":false},{"pmid":"22826316","id":"PMC_22826316","title":"The protein tyrosine phosphatase SHP-1 regulates phagolysosome biogenesis.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22826316","citation_count":22,"is_preprint":false},{"pmid":"25426871","id":"PMC_25426871","title":"Identification of the link between the hypothalamo-pituitary axis and the testicular orphan nuclear receptor NR0B2 in adult male mice.","date":"2014","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25426871","citation_count":21,"is_preprint":false},{"pmid":"22512561","id":"PMC_22512561","title":"SHP-2 regulates growth factor dependent vascular signalling and function.","date":"2014","source":"Mini reviews in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22512561","citation_count":21,"is_preprint":false},{"pmid":"18007036","id":"PMC_18007036","title":"Interaction between the androgen receptor and a segment of its corepressor SHP.","date":"2007","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/18007036","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47898,"output_tokens":5377,"usd":0.112174,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13914,"output_tokens":5233,"usd":0.100197,"stage2_stop_reason":"end_turn"},"total_usd":0.212371,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"SHP (NR0B2) lacks a conventional DNA-binding domain but contains novel receptor interaction and repressor domains. The central region (amino acids 92–148) mediates interaction with RXRα, thyroid hormone receptor, and retinoic acid receptor; the C-terminal region constitutes an autonomous repressor domain distinct from N-CoR-binding sequences. SHP did not interact with N-CoR in yeast or mammalian two-hybrid systems.\",\n      \"method\": \"Mammalian two-hybrid, yeast two-hybrid, in vitro binding (deletion and domain mapping), transient transfection repressor assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (yeast two-hybrid, mammalian two-hybrid, in vitro binding, transactivation assays) in a focused mechanistic study\",\n      \"pmids\": [\"9372944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The SHP gene (Nr0b2) is composed of two exons with a single intron; it is located at human chromosome 1p36.1. Tissue-specific expression is highest in fetal liver, fetal adrenal gland, adult spleen, and adult small intestine, and promoter activity is higher in adrenal-derived cells than HeLa cells.\",\n      \"method\": \"Genomic library screening, Southern blot, FISH, primer extension, transient transfection promoter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal structural/genomic methods establishing gene organization and tissue expression\",\n      \"pmids\": [\"9603951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SHP inhibits androgen receptor (AR)-mediated transcription by up to 97%. Interaction requires AR ligand and is mediated by SHP LxxLL (LXXI/LL) motifs binding the AR ligand-binding domain (AR-LBD). SHP also interacts with the AR N-terminal domain (AR-NTD), stabilizing the overall AR–SHP interaction. SHP competes with AR coactivators (FHL2, TIF2) and inhibits both AR-LBD- and AR-NTD-dependent transactivation.\",\n      \"method\": \"Mammalian two-hybrid, GST pull-down, co-immunoprecipitation, luciferase reporter transactivation assay, competition with coactivators\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal binding and functional assays in a single focused study\",\n      \"pmids\": [\"11735420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FXR activation induces SHP expression, and increased SHP protein associates with LRH-1 (liver receptor homolog-1), an obligate transcriptional activator of CYP7A1 (cholesterol-7α-hydroxylase), thereby repressing CYP7A1 expression and bile acid synthesis.\",\n      \"method\": \"Transient transfection reporter assays, co-immunoprecipitation, cited functional studies\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mechanistic model well-established in the field, but this specific abstract is a review summarizing primary data; moderate confidence based on review summary\",\n      \"pmids\": [\"11907135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SHP represses transcription by recruiting histone deacetylases (HDACs). Two core repressive domains were mapped to amino acids 170–210 and 210–240 of SHP. SHP directly interacts with HDAC1, and SHP, AR, and HDAC1 form a ternary complex. HDAC inhibitor trichostatin A (TSA) reverses SHP-mediated repression of both AR and ERα transactivation.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, luciferase reporter assays, TSA pharmacological inhibition, deletion mapping\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, GST pulldown, and functional rescue with pharmacological inhibitor; multiple orthogonal methods\",\n      \"pmids\": [\"15835920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SHP (NR0B2) acts as an inducible, tissue-specific transcriptional corepressor by directly binding multiple nuclear receptors through its LxxLL-related motifs and suppressing their transactivation. SHP lacks a DNA-binding domain but retains a ligand-binding domain-like region.\",\n      \"method\": \"Review synthesizing two-hybrid, Co-IP, reporter, and in vivo data from multiple primary studies\",\n      \"journal\": \"Trends in endocrinology and metabolism: TEM\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — review of replicated findings; mechanism established across multiple labs but this citation is a review\",\n      \"pmids\": [\"16275121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DAX1 (NR0B1) and SHP (NR0B2) form individual homodimers as well as DAX1–SHP heterodimers in the nucleus of mammalian cells. DAX1 homodimerization involves LXXLL motifs and the AF-2 domain; SHP homodimers dissociate upon heterodimerization with ligand-activated ERα. DAX1–SHP heterodimerization also involves the LXXLL motifs and AF-2 domain of DAX1.\",\n      \"method\": \"Co-immunoprecipitation, mammalian two-hybrid, subcellular fractionation/localization, BRET assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and two-hybrid in mammalian cells; single lab\",\n      \"pmids\": [\"16709599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SMILE (SHP-interacting leucine zipper protein) was identified as a new SHP-interacting protein. The N-terminus of SHP and the middle region of SMILE-L mediate their interaction. SMILE isoforms regulate SHP-dependent repression of estrogen receptor transactivation in a cell-type-specific manner; in breast cancer cell lines, SMILE enhances SHP repression of ERα and downregulates ERα-target E2F1 expression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization (immunofluorescence), siRNA knockdown, adenoviral overexpression, reporter assays, domain-mapping mutagenesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, Co-IP, co-localization, siRNA, reporter) in a single focused study\",\n      \"pmids\": [\"18657049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SHP activates miR-206 expression through a cascade dual-inhibitory mechanism: SHP inhibits ERRγ transcriptional activity, leading to decreased YY1 expression; reduced YY1 de-represses AP1 (c-Jun/c-Fos) activity, which then activates the miR-206 promoter. ChIP confirmed physical association of AP1 (c-Jun), YY1, and ERRγ with respective promoters.\",\n      \"method\": \"Microarray, real-time PCR, RACE, luciferase reporter assay, ChIP, siRNA knockdown, forced expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, siRNA, reporter assays, overexpression) establishing cascade in single lab\",\n      \"pmids\": [\"19721712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SHP (NR0B2) has a cytoplasmic function: it localizes to mitochondria where it binds Bcl-2, disrupts Bcl-2/Bid interaction, and induces cytochrome c release and apoptosis. AHPN promotes SHP translocation from nucleus to mitochondria. SHP activation inhibits peritoneal pancreatic tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, confocal microscopy, cytochrome c release assay, tumor growth assay, pharmacological induction (AHPN)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, fractionation, and imaging in a single lab; single study\",\n      \"pmids\": [\"20065042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Two novel missense mutations of SHP (R38H, K170N) impair nuclear translocation. K170N makes SHP more susceptible to ubiquitin-mediated degradation, blocks SHP acetylation, and abolishes repressive activity on ERRγ and HNF4α but not LRH-1. G171A stabilizes nuclear receptor boxes. K170N impairs recruitment of SHP, HNF4α, HDAC1, and HDAC3 to the apoCIII promoter. Molecular dynamics simulations show G171A stabilizes and K170N destabilizes structural elements of the receptor.\",\n      \"method\": \"Mutant expression, nuclear translocation assay, ubiquitination assay, acetylation assay, reporter assays, ChIP, molecular dynamics simulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ChIP, reporter, structural simulation, PTM assays) establishing functional consequences of specific residues\",\n      \"pmids\": [\"20516075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FXR activates SHP (Nr0b2) transcription through two FXR response elements (FXRREs): one in the proximal promoter and a novel one in the 3'-enhancer region. These two FXRREs interact via head-to-tail chromatin looping to increase SHP transcription efficiency.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, luciferase reporter assay, site-directed mutagenesis, chromatin conformation capture (3C) assay\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct demonstration of chromatin looping by 3C, supported by ChIP-seq and mutagenesis\",\n      \"pmids\": [\"20444884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SHP represses Dnmt1 expression by inhibiting ERRγ transactivation; ERRγ binds directly to ERE1/ERE2 response elements in the Dnmt1 promoter and activates transcription, while SHP diminishes ERRγ recruitment and shifts local chromatin to an inactive conformation. SHP-knockout mice show increased Dnmt1 expression; SHP-transgenic mice show decreased Dnmt1.\",\n      \"method\": \"Reporter assays, ChIP, co-immunoprecipitation, SHP-KO and SHP-transgenic mouse models, Western blot\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, Co-IP, reporter, and in vivo genetic models provide convergent evidence\",\n      \"pmids\": [\"21459093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SHP inhibits zinc-induced Dnmt1 expression by antagonizing MTF-1 (metal-responsive transcription factor-1). Zinc induces MTF-1 occupancy on the Dnmt1 promoter; SHP represses MTF-1 expression and abolishes zinc-mediated chromatin changes at the Dnmt1 promoter. SHP-KO mice have increased Dnmt1; SHP-transgenic mice have decreased Dnmt1.\",\n      \"method\": \"Reporter assays, ChIP, co-immunoprecipitation, SHP-KO and SHP-transgenic mice, Western blot\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, Co-IP, reporter, in vivo KO/TG models)\",\n      \"pmids\": [\"22362755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of SHP in complex with EID1 reveals an unexpected binding site at the N-terminus of the receptor (mimicking helix H1 of the nuclear receptor LBD), distinct from the classical C-terminal H12 cofactor-binding site. Mutations at the SHP–EID1 interface diminish their interaction and reduce SHP repressor activity.\",\n      \"method\": \"X-ray crystallography, mutagenesis, in vitro binding, reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure solved and validated by mutagenesis and functional assays\",\n      \"pmids\": [\"24379397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"G93D missense mutation of SHP (NR0B2) shows reduced in vitro inhibition of HNF-4α transactivation of the HNF-1α promoter when expressed in MIN6-m9 and HepG2 cells, demonstrating that the G93 residue contributes to SHP repressor function.\",\n      \"method\": \"SSCP/heteroduplex mutation analysis, transient transfection reporter assay in MIN6-m9 and HepG2 cells\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay in two cell lines, single lab\",\n      \"pmids\": [\"15459958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the AR ligand-binding domain in complex with a 14-mer peptide from SHP NR Box 2 (LKKIL motif) reveals that SHP binds the same hydrophobic groove on AR used by coactivators. Only NR Box 2 of SHP formed a crystal complex with AR-LBD under the conditions tested, and SHP inhibits AR by competing with coactivators at this site.\",\n      \"method\": \"X-ray crystallography (AR-LBD/SHP peptide co-crystal), structural comparison with coactivator-bound AR complexes\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with defined binding mode; single study/lab\",\n      \"pmids\": [\"18007036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SHP interacts with FOXA1 to oscillatorily regulate homocysteine metabolism genes (Bhmt, cystathionine γ-lyase). SHP inhibits FOXA1-mediated transcriptional activation of Bhmt and cystathionine γ-lyase, controlling oscillatory production of S-adenosylmethionine, betaine, and related metabolites. SHP-null mice have altered circadian timing of homocysteine metabolism gene expression and are protected from ethanol- and homocysteine-induced hyperhomocysteinemia.\",\n      \"method\": \"RNA-seq, metabolomics, ChIP, immunoblot, SHP-null mouse model, gene expression (qPCR), 24-h light-dark cycle sampling\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, SHP-KO mice, and metabolomics provide multiple orthogonal lines of evidence for this interaction and pathway\",\n      \"pmids\": [\"25701738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AhR activates Pemt and Gnmt (one-carbon cycle genes regulating PC/SAM levels) in the early fed state; SHP, activated by FGF15 signaling in the late fed state, blocks this AhR-mediated induction. SHP-null mice fail to suppress AhR-driven Pemt/Gnmt expression, altering PC and SAM levels. Adenoviral AhR in obese mice exacerbates steatosis, and co-expression of SHP blunts this effect.\",\n      \"method\": \"SHP-null mouse model, adenoviral overexpression, ChIP, reporter assays, metabolomic analysis, immunoblot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model, adenoviral rescue, ChIP, and metabolomics provide convergent mechanistic evidence\",\n      \"pmids\": [\"29416063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NF-κB p65 recruits SHP (NR0B2) to the PDCD5 gene promoter; a SHP/NF-κB p65 complex is found on the PDCD5 gene, and 3-Cl-AHPC-mediated apoptosis increases SHP mRNA/protein and the SHP/p65 interaction. PDCD5 induction triggers apoptosis via increased Bax and cytochrome c release.\",\n      \"method\": \"ChIP-on-chip, ChIP, co-immunoprecipitation, reporter assay, siRNA knockdown, overexpression, Western blot\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP identify the complex; single lab\",\n      \"pmids\": [\"24343129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LH/CG represses Nr0b2 (SHP) expression in testicular Leydig cells through the protein kinase A–AMP protein kinase (PKA–AMPK) pathway. NR0B2 mediates the repression of testosterone synthesis and subsequent germ cell apoptosis induced by anti-GnRH compounds, establishing a functional link between the hypothalamo-pituitary axis and NR0B2 in testicular androgen metabolism.\",\n      \"method\": \"Transgenic NR0B2-null mouse model, pharmacological pathway inhibitors (PKA, AMPK), hormone treatment, testosterone measurement, TUNEL assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with defined hormonal pathway; single lab\",\n      \"pmids\": [\"25426871\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR0B2/SHP is an atypical nuclear receptor that lacks a DNA-binding domain but contains LxxLL-like motifs and a ligand-binding domain-like region; it functions as an inducible transcriptional corepressor by directly binding numerous nuclear receptors (including RXRα, AR, ERα, LRH-1, HNF4α, ERRγ) and recruiting HDAC1/3 complexes, and by physically interacting with non-receptor partners (EID1, SMILE, FOXA1, MTF-1, NF-κB p65, AhR) to suppress target gene transcription—including bile acid (CYP7A1), lipid (SREBP1c, Dnmt1, Pemt, Gnmt), and steroid hormone pathway genes—while also possessing a cytoplasmic apoptotic function through mitochondrial translocation and Bcl-2 binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR0B2/SHP is an atypical, inducible nuclear receptor that functions principally as a transcriptional corepressor, lacking a conventional DNA-binding domain while retaining a receptor-interaction region and an autonomous C-terminal repressor domain [#0]. It silences target genes by directly binding the ligand-binding domains of partner nuclear receptors through LxxLL-related motifs (NR boxes) that occupy the same hydrophobic coactivator groove, thereby competing out coactivators—demonstrated structurally for androgen receptor, where SHP NR Box 2 docks into the AR-LBD groove used by FHL2 and TIF2 [#2, #16]. SHP enforces repression by recruiting histone deacetylases, forming ternary complexes with target receptors and HDAC1/HDAC3 that can be reversed pharmacologically with the HDAC inhibitor TSA [#4, #10]. Beyond classical receptor binding, SHP engages non-receptor partners: a crystal structure with EID1 revealed a second, N-terminal interaction surface mimicking helix H1 of the nuclear receptor LBD, distinct from the C-terminal cofactor site [#14], and SHP also partners with SMILE and FOXA1 to modulate repression in a cell-type- and tissue-specific manner [#7, #17]. As an FGF/FXR-inducible factor—its own transcription driven by FXR through chromatin-looping FXR response elements [#11]—SHP integrates into bile acid and lipid metabolic control, repressing LRH-1-driven CYP7A1 and bile acid synthesis [#3] and suppressing one-carbon and lipid genes (Dnmt1, Pemt, Gnmt) by antagonizing ERRγ, MTF-1, and AhR [#12, #13, #18]. SHP additionally possesses a cytoplasmic apoptotic function: upon pharmacological induction it translocates to mitochondria, binds Bcl-2, disrupts Bcl-2/Bid interaction, and triggers cytochrome c release [#9]. Missense mutations (G93D, R38H, K170N) that impair repressor activity or nuclear translocation establish specific residues required for SHP function [#10, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established SHP as a structurally unconventional nuclear receptor—lacking a DNA-binding domain but carrying distinct receptor-interaction and repressor modules—reframing how it could act on transcription.\",\n      \"evidence\": \"Domain mapping by yeast/mammalian two-hybrid and in vitro binding with transactivation assays\",\n      \"pmids\": [\"9372944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of repression (cofactor recruitment) not yet defined\", \"Physiological target genes unidentified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the gene's two-exon structure, chromosomal location, and tissue-restricted expression, anchoring SHP in liver, adrenal, and intestinal biology.\",\n      \"evidence\": \"Genomic library screening, FISH, primer extension, promoter assays\",\n      \"pmids\": [\"9603951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish the upstream signals controlling tissue-specific induction\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed SHP represses androgen receptor by competing with coactivators via LxxLL motifs, extending its corepressor role to steroid hormone signaling.\",\n      \"evidence\": \"Two-hybrid, GST pull-down, Co-IP, reporter and coactivator competition assays\",\n      \"pmids\": [\"11735420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of competition not yet resolved\", \"Did not address downstream effector recruitment\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed SHP in the FXR-bile acid feedback loop, where it represses LRH-1 to shut down CYP7A1 and bile acid synthesis.\",\n      \"evidence\": \"Reporter assays and Co-IP summarized in a review of primary data\",\n      \"pmids\": [\"11907135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Summarized from review rather than primary data\", \"Chromatin-level mechanism on CYP7A1 not detailed here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that a single residue (G93) is required for SHP repression of HNF-4α, linking specific structure to repressor output.\",\n      \"evidence\": \"Mutation analysis and reporter assays in MIN6-m9 and HepG2 cells\",\n      \"pmids\": [\"15459958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional assay in cell lines only; in vivo consequence not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified HDAC recruitment as the effector mechanism of SHP repression, mapping repressive subdomains and showing AR/SHP/HDAC1 ternary complex formation reversible by TSA.\",\n      \"evidence\": \"GST pull-down, Co-IP, reporter assays, TSA inhibition, deletion mapping\",\n      \"pmids\": [\"15835920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC recruitment is universal across all SHP target receptors not established\", \"Additional corepressor partners not excluded\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed SHP can homodimerize and heterodimerize with DAX1, with ligand-activated ERα dissociating SHP homodimers, adding a dimerization layer to its regulation.\",\n      \"evidence\": \"Co-IP, mammalian two-hybrid, fractionation, BRET in mammalian cells\",\n      \"pmids\": [\"16709599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of homo- vs heterodimer not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified SMILE as a SHP partner that tunes SHP repression of ERα in a cell-type-specific manner, expanding the non-receptor partner repertoire.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, co-localization, siRNA, reporter, domain mapping\",\n      \"pmids\": [\"18657049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SHP-SMILE interaction unresolved\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed that SHP can indirectly activate gene expression through a dual-inhibitory ERRγ→YY1→AP1 cascade driving miR-206, showing its repression can yield net activation downstream.\",\n      \"evidence\": \"Microarray, qPCR, RACE, reporter, ChIP, siLP, forced expression\",\n      \"pmids\": [\"19721712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of miR-206 regulation by SHP not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established a cytoplasmic, mitochondrial apoptotic function for SHP via Bcl-2 binding and cytochrome c release, distinct from its nuclear corepressor role.\",\n      \"evidence\": \"Co-IP, fractionation, confocal imaging, cytochrome c release, tumor growth assays with AHPN induction\",\n      \"pmids\": [\"20065042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal triggering nuclear-to-mitochondrial translocation incompletely defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped how disease-associated residues (R38H, K170N, G171A) control SHP nuclear translocation, acetylation, stability, and target-selective repression, connecting residue chemistry to function.\",\n      \"evidence\": \"Mutant expression, translocation/ubiquitination/acetylation assays, ChIP, reporter, molecular dynamics\",\n      \"pmids\": [\"20516075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why repression of LRH-1 is spared by K170N not mechanistically explained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined how SHP's own transcription is amplified by FXR through two response elements brought together by chromatin looping, explaining its rapid inducibility.\",\n      \"evidence\": \"ChIP-seq, ChIP-qPCR, reporter, mutagenesis, 3C chromatin conformation capture\",\n      \"pmids\": [\"20444884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Looping factors mediating the FXRRE interaction not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed SHP controls DNA methylation machinery by repressing Dnmt1 through ERRγ antagonism, confirmed in KO and transgenic mice.\",\n      \"evidence\": \"Reporter, ChIP, Co-IP, SHP-KO and SHP-transgenic mice, Western blot\",\n      \"pmids\": [\"21459093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream methylation targets affected not catalogued\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended SHP's Dnmt1 control to antagonism of the metal-responsive factor MTF-1, showing it integrates zinc signaling into epigenetic regulation.\",\n      \"evidence\": \"Reporter, ChIP, Co-IP, SHP-KO and transgenic mice, Western blot\",\n      \"pmids\": [\"22362755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect repression of MTF-1 not fully separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Solved a crystal structure of SHP bound to EID1, revealing a non-canonical N-terminal interaction surface distinct from the classical H12 cofactor site.\",\n      \"evidence\": \"X-ray crystallography, mutagenesis, in vitro binding, reporter assay\",\n      \"pmids\": [\"24379397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other partners use this same N-terminal site not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided a structural view of how SHP NR Box 2 occupies the AR coactivator groove, explaining coactivator competition at atomic resolution.\",\n      \"evidence\": \"X-ray crystallography of AR-LBD/SHP peptide complex, structural comparison\",\n      \"pmids\": [\"18007036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of NR Box 1 and N-terminal contacts to full-length binding not captured in peptide co-crystal\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked SHP to NF-κB-driven apoptosis, showing p65 recruits SHP to the PDCD5 promoter to promote a pro-apoptotic program.\",\n      \"evidence\": \"ChIP-on-chip, ChIP, Co-IP, reporter, siRNA, overexpression, Western blot\",\n      \"pmids\": [\"24343129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SHP activates or represses PDCD5 in this context not fully clarified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed Nr0b2 under hypothalamo-pituitary control via LH/CG-PKA-AMPK signaling in Leydig cells, mediating testosterone repression and germ cell apoptosis.\",\n      \"evidence\": \"NR0B2-null mice, PKA/AMPK inhibitors, hormone treatment, testosterone measurement, TUNEL\",\n      \"pmids\": [\"25426871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SHP target genes in steroidogenesis not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed SHP interacts with FOXA1 to impose circadian, oscillatory control over homocysteine metabolism genes, protecting against hyperhomocysteinemia.\",\n      \"evidence\": \"RNA-seq, metabolomics, ChIP, immunoblot, SHP-null mice, time-course sampling\",\n      \"pmids\": [\"25701738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling SHP to circadian clock inputs not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated SHP, induced by FGF15 in the late fed state, antagonizes AhR-driven Pemt/Gnmt one-carbon gene induction, positioning SHP as a temporal switch in hepatic lipid/methyl metabolism.\",\n      \"evidence\": \"SHP-null mice, adenoviral overexpression/rescue, ChIP, reporter, metabolomics\",\n      \"pmids\": [\"29416063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SHP-AhR physical contact vs competition for promoter not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SHP's nuclear corepressor activity and its cytoplasmic mitochondrial pro-apoptotic function are coordinated, and what signals govern its subcellular partitioning, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Translocation signal and trigger not defined\", \"Integration of metabolic, apoptotic, and circadian roles within single cells unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 16]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 12, 13, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 8, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RXRA\", \"AR\", \"LRH-1\", \"HNF4A\", \"ERRG\", \"HDAC1\", \"EID1\", \"FOXA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}