Affinage

NR0B2

Nuclear receptor subfamily 0 group B member 2 · UniProt Q15466

Length
257 aa
Mass
28.1 kDa
Annotated
2026-04-29
100 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR0B2 (SHP) is an atypical orphan nuclear receptor that lacks a DNA-binding domain and functions as a versatile transcriptional corepressor in hepatic bile acid, lipid, and one-carbon metabolism, as well as in bone remodeling and inflammatory signaling. SHP is transcriptionally induced by FXR through chromatin looping between proximal and distal FXR response elements, and is post-translationally activated by FGF15/19-mediated phosphorylation, which enables recruitment of epigenetic silencing machinery including SIRT1 histone deacetylase and DNMT3A DNA methyltransferase to target gene promoters (PMID:20444884, PMID:20375098, PMID:33235221). SHP binds a broad array of nuclear receptors (LRH-1, GR, ERα, AR, ERRγ, HNF-4α) and transcription factors (JunD/AP-1, FOXA1, p65) through its NR-box motifs, competing with coactivators at the AF-2 surface to repress transcription of genes controlling bile acid synthesis (CYP7A1), lipogenesis (SREBP-1c targets), gluconeogenesis (PEPCK), and homocysteine metabolism (Bhmt, Cth) (PMID:15723037, PMID:15146238, PMID:12324453, PMID:25701738). SHP protein stability is regulated by ubiquitination and acetylation at Lys-170, and naturally occurring variants such as K170N and R38H impair nuclear translocation and corepressor function (PMID:20516075).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    Establishing that SHP functions as a ligand-modulated inhibitor of steroid receptors answered the question of how an orphan NR lacking a DBD exerts transcriptional effects — SHP directly binds ERα via NR-box motifs and represses estrogen-dependent transactivation.

    Evidence Mammalian/yeast two-hybrid, GST pull-down, and reporter assays mapping NR-box-dependent SHP–ERα interaction

    PMID:9773978

    Open questions at the time
    • Endogenous ligand for SHP's LBD pocket not identified
    • In vivo relevance of SHP–ERα interaction not tested
  2. 2001 High

    Demonstrating that SHP inhibits AR through both LBD- and NTD-dependent interactions and competes with coactivators FHL2/TIF2 broadened the corepressor model beyond steroid receptor LBD contacts.

    Evidence Two-hybrid, deletion mapping, reporter assays, and coactivator competition assays

    PMID:11735420

    Open questions at the time
    • Physiological context of SHP–AR antagonism undefined
    • No in vivo data
  3. 2002 High

    Showing that SHP antagonizes GR by competing with PGC-1 and causing intranuclear redistribution of GR connected SHP to gluconeogenic gene regulation (PEPCK).

    Evidence Mammalian/yeast two-hybrid, GFP live imaging, reporter assays with inhibition-deficient SHP mutants

    PMID:12324453

    Open questions at the time
    • In vivo metabolic consequence of SHP–GR antagonism not demonstrated
  4. 2004 High

    Genetic epistasis with SHP-null and LXRα/β-null mice established that FXR-induced SHP is required for repression of SREBP-1c and triglyceride lowering, positioning SHP as an essential node in the bile acid–lipogenesis regulatory axis.

    Evidence SHP−/− and LXRα/β−/− knockout mice, molecular assays, hypertriglyceridemia models

    PMID:15146238

    Open questions at the time
    • Mechanism by which SHP inhibits LXRα-mediated SREBP-1c transcription not fully resolved at the chromatin level
  5. 2004 High

    Identification of SHP–JunD binding and inhibition of AP-1 activity in hepatic stellate cells extended SHP's repressor role beyond nuclear receptors to non-NR transcription factors and linked it to protection against liver fibrosis.

    Evidence Retroviral overexpression and siRNA knockdown in HSC-T6 cells, protein binding assays, rodent fibrosis models

    PMID:15521018

    Open questions at the time
    • Direct structural basis of SHP–JunD interaction unknown
  6. 2005 High

    The 1.9 Å crystal structure of SHP NR-box 1 bound to the LRH-1 AF-2 surface provided the first atomic-level explanation for how SHP mimics coactivator binding to repress target NRs.

    Evidence X-ray crystallography, mass spectrometry, mutagenesis, in vivo reporter assays

    PMID:15723037

    Open questions at the time
    • Structure of full-length SHP or its complex with other NR partners not determined
  7. 2009 High

    Discovery that SHP activates miR-206 through a cascade (SHP→ERRγ→YY1→AP-1) revealed SHP can upregulate gene expression indirectly through serial repression.

    Evidence Microarray, ChIP, siRNA knockdown, reporter assays

    PMID:19721712

    Open questions at the time
    • Physiological significance of miR-206 regulation by SHP not validated in vivo
  8. 2010 High

    Multiple 2010 studies resolved how SHP's own transcription is controlled (FXR-mediated chromatin looping), how SHP represses chromatin (SIRT1 recruitment to deacetylate H3/H4), and how post-translational modifications (ubiquitination, acetylation at K170) regulate SHP stability and partner selectivity.

    Evidence ChIP-seq, 3C chromatin conformation capture, Co-IP/co-localization, ubiquitination/acetylation assays, SHP−/− mice, molecular dynamics, SNP functional analysis

    PMID:20375098 PMID:20444884 PMID:20516075

    Open questions at the time
    • Kinase responsible for SHP phosphorylation not yet assigned in this context
    • Whether K170 acetylation is enzymatically reversible in vivo unknown
  9. 2010 High

    SHP−/− mice exhibit decreased bone mass and reduced osteoblast numbers; SHP promotes Runx2 transactivation by displacing HDAC4 from the osteocalcin promoter, establishing a coactivator-like role for SHP in bone.

    Evidence Co-IP, ChIP, reporter assays, SHP−/− mice, ectopic bone formation assay

    PMID:19594294

    Open questions at the time
    • Upstream signals activating SHP in osteoblasts unidentified
    • Whether SHP–Runx2 interaction is NR-box-dependent not shown
  10. 2011 High

    Double knockout of Fxr and Shp caused juvenile cholestasis more severe than either single KO, with ectopic Cyp17a1 induction and elevated 17-OHP, revealing non-overlapping protective functions of FXR and SHP.

    Evidence Fxr−/−;Shp−/− double KO mice, gene expression, serum metabolites, pharmacological 17-OHP challenge

    PMID:21123943

    Open questions at the time
    • Mechanism by which SHP represses Cyp17a1 not determined
  11. 2013 High

    The SHP–EID1 crystal structure revealed a non-canonical cofactor-binding site at the N-terminal helix H1 of SHP's LBD, distinct from the classical AF-2 groove, expanding the structural repertoire of SHP-mediated repression.

    Evidence X-ray crystallography, mutagenesis, protein interaction and reporter assays

    PMID:24379397

    Open questions at the time
    • Whether the H1 site operates simultaneously with the AF-2 site in a ternary complex is unknown
  12. 2015 High

    SHP was shown to govern oscillatory homocysteine homeostasis by inhibiting FOXA1 transactivation of Bhmt and Cth, connecting SHP to one-carbon metabolism and linking its loss to ethanol-induced hyperhomocysteinemia.

    Evidence SHP-null and BHMT-null mice, RNA-seq, ChIP, metabolomics

    PMID:25701738

    Open questions at the time
    • Whether circadian regulation of SHP drives the oscillatory pattern not tested
  13. 2018 High

    SHP was placed into a temporal feeding-cycle circuit: insulin/PKB-driven AhR activates Pemt/Gnmt in the early fed state, while FGF15-activated SHP blocks this induction in the late fed state, controlling phosphatidylcholine and SAM levels.

    Evidence SHP-null and FGF15-null mice, ChIP, metabolomics

    PMID:29416063

    Open questions at the time
    • Direct SHP–AhR physical interaction not demonstrated
  14. 2020 High

    The FGF15/19–SHP–DNMT3A epigenetic axis was defined: FGF15/19-mediated phosphorylation of SHP enables DNMT3A recruitment to lipogenic promoters, causing DNA methylation-dependent repression in the late fed state.

    Evidence Comparative genomics, SHP-KO mice, ChIP, bisulfite sequencing, phosphorylation assays, DNMT3A-KO validation

    PMID:33235221

    Open questions at the time
    • Specific phosphorylation site(s) on SHP mediating DNMT3A recruitment not mapped
    • Reversibility and dynamics of DNA methylation marks unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of any endogenous SHP ligand, the full-length SHP structure, how SHP switches between corepressor and apparent coactivator roles (e.g., Runx2), and the tissue-specific regulation of SHP post-translational modifications.
  • No endogenous ligand identified
  • No full-length SHP structure
  • Mechanism governing context-dependent coactivator vs corepressor activity unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0140110 transcription regulator activity 6
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 2
Partners
ARDNMT3AESR1ESRRGNR1H4NR3C1NR5A2SIRT1

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Bile acid activation of FXR induces SHP (NR0B2) expression, and SHP is required for FXR-mediated repression of SREBP-1c and its lipogenic target genes, thereby lowering triglyceride levels. Genetic epistasis using SHP-null and LXRα/β-null mice demonstrated that both SHP and LXRα/β are essential for this repressive pathway. Mouse knockout models (SHP-/-, LXRα/β-/-), molecular and cellular assays, animal models of hypertriglyceridemia The Journal of clinical investigation High 15146238
2004 SHP (NR0B2) is expressed in hepatic stellate cells (HSCs) and, downstream of FXR activation, directly binds JunD and inhibits AP-1 DNA binding induced by thrombin, thereby protecting against liver fibrosis. This was demonstrated using SHP-overexpressing and SHP-deficient HSC-T6 cell lines. Retroviral overexpression and siRNA knockdown of SHP in HSC-T6 cells; protein binding assays; in vivo rodent fibrosis models Gastroenterology High 15521018
2005 Crystal structure of the hLRH-1 ligand-binding domain in complex with the NR box 1 motif of human SHP (NR0B2) at 1.9 Å resolution revealed that SHP contacts the AF-2 region of hLRH-1 using selective structural motifs, establishing the structural basis for SHP-mediated corepression of LRH-1. X-ray crystallography (1.9 Å), mass spectrometry, in vivo reporter assays with LBD pocket mutations Nature structural & molecular biology High 15723037
2002 SHP (NR0B2) interacts with and potently inhibits glucocorticoid receptor (GR) transcriptional activity via a functional second NR-box within SHP. SHP antagonizes the GR coactivator PGC-1 and represses the PEPCK promoter. Co-expression of GFP-tagged GR with SHP caused intranuclear redistribution of GR, an effect requiring SHP's inhibitory function. Mammalian and yeast two-hybrid, transient cotransfection assays, GFP imaging, inhibition-deficient SHP mutants The Journal of biological chemistry High 12324453
1998 SHP (NR0B2) interacts with estrogen receptor alpha (ERα) in an agonist-dependent manner via its NR-box motifs (the same domain used to interact with RXR and TR), and inhibits estradiol-dependent ERα transcriptional activation ~5-fold. SHP also interacts with ERβ in a ligand-independent manner. Mammalian and yeast two-hybrid, GST pull-down, deletion mutant mapping, transient cotransfection reporter assays Molecular endocrinology High 9773978
2001 SHP (NR0B2) inhibits androgen receptor (AR) transcriptional activity by up to 97% through ligand-dependent interaction with the AR ligand-binding domain via LXXI/LL motifs, and also interacts with the AR N-terminal domain, enabling inhibition of both LBD- and NTD-dependent transactivation. SHP competes with AR coactivators FHL2 and TIF2. Two-hybrid assays, deletion mutant analysis, transient cotransfection reporter assays, coactivator competition assays Biochemistry High 11735420
2010 SHP (NR0B2) recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation in an NR-specific manner. SHP and SIRT1 co-immunoprecipitate and co-localize in vivo. SIRT1 deacetylates histones H3 and H4 at LRH-1 target gene promoters (CYP7A1, SHP itself), and inhibition of SIRT1 reverses SHP-mediated repression of bile acid synthesis. Co-IP, co-localization, ChIP assays, dominant-negative SIRT1, siRNA knockdown, luciferase reporter assays Nucleic acids research High 20375098
2013 Crystal structure of SHP (NR0B2) in complex with EID1 revealed that EID1 binds an unexpected N-terminal site on SHP (mimicking helix H1 of the NR LBD), distinct from the classical C-terminal H12 cofactor-binding site. Mutations at this interface diminish SHP-EID1 interactions and impair SHP repressor activity. X-ray crystallography, mutagenesis, protein interaction assays, functional reporter assays Proceedings of the National Academy of Sciences of the United States of America High 24379397
2020 FGF15/19 activates SHP (NR0B2) via phosphorylation, and phosphorylated SHP recruits DNMT3A to lipogenic gene promoters, leading to epigenetic repression via DNA methylation. This FGF15/19-SHP-DNMT3A axis physiologically represses hepatic lipogenesis in the late fed state. Comparative genomics, adenoviral overexpression, SHP knockout mice, ChIP, bisulfite sequencing, phosphorylation assays, DNMT3A-knockout validation Nature communications High 33235221
2010 FXR activates SHP (NR0B2) transcription through two FXR response elements (FXRREs): one in the proximal promoter and one in a novel downstream 3'-enhancer of the Nr0b2 gene. These two FXRREs interact to form a head-to-tail chromatin loop as detected by chromatin conformation capture assay, enhancing transcription efficiency. ChIP-seq, ChIP-qPCR, chromatin conformation capture (3C), luciferase reporter assays, site-directed mutagenesis Molecular endocrinology High 20444884
2010 Combined deletion of both Fxr and Shp (NR0B2) in mice causes juvenile-onset cholestasis more severe than either single knockout, demonstrating that FXR and SHP have partially non-overlapping functions. The double knockout induced Cyp17a1, elevated 17-hydroxyprogesterone (17-OHP), and 17-OHP treatment alone was sufficient to reproduce liver injury. Double knockout mouse model, gene expression analysis, serum metabolite measurement, pharmacological 17-OHP treatment The Journal of clinical investigation High 21123943
2002 SHP (NR0B2) inhibits CYP7A1 transcription by associating with LRH-1 (liver receptor homolog-1), an obligate transcriptional activator of CYP7A1, thereby repressing bile acid synthesis downstream of FXR-induced SHP expression. Molecular and cellular studies reviewed; interaction assays and transcriptional reporter assays cited across multiple studies Journal of lipid research Medium 11907135
2009 SHP (NR0B2) activates miR-206 expression through a cascade dual inhibitory mechanism: SHP inhibits ERRγ, which reduces YY1 expression, which in turn de-represses AP-1 activity on the miR-206 promoter. ChIP confirmed ERRγ binding to the YY1 promoter and AP1/YY1 binding to the miR-206 promoter. Microarray profiling, RACE, ChIP assays, siRNA knockdown, promoter reporter assays, forced expression PloS one High 19721712
2010 SHP (NR0B2) polymorphisms R38H and K170N impair nuclear translocation. K170N increases susceptibility to ubiquitination-mediated degradation and blocks SHP acetylation, leading to loss of repressive activity on ERRγ and HNF4α (but not LRH-1). K170N also impairs recruitment of SHP, HNF4α, HDAC1, and HDAC3 to the apoCIII promoter. SNP identification, nuclear localization assays, ubiquitination assays, acetylation assays, ChIP, reporter assays, molecular dynamics simulation The Journal of biological chemistry High 20516075
2011 SHP (NR0B2) represses Dnmt1 expression by inhibiting ERRγ transactivation at ERRγ response elements in the Dnmt1 promoter, reducing ERRγ recruitment and shifting local chromatin to an inactive conformation. Luciferase reporter assays, ChIP assays, ERRγ and SHP overexpression/knockdown FEBS letters Medium 21459093
2010 SHP (NR0B2) overexpression in adipose tissue increases body weight and adiposity in young transgenic mice, impairs adaptive thermogenesis on high-fat diet, and decreases energy expenditure and physical activity, establishing a direct role for adipose SHP in metabolic regulation. Fat-specific SHP transgenic mice, metabolic rate measurement, cold-exposure studies, high-fat diet feeding, brown fat ultrastructural analysis American journal of physiology. Endocrinology and metabolism Medium 20124506
2010 SHP (NR0B2) physically interacts with Runx2 on the osteocalcin gene promoter and increases Runx2 transactivity by competing with HDAC4, which normally inhibits Runx2 DNA binding. SHP-/- mice show decreased bone mass and reduced osteoblast numbers. Co-IP, ChIP, reporter assays, SHP-/- mice, adenoviral overexpression/knockdown, ectopic bone formation assay Journal of bone and mineral research High 19594294
2015 SHP (NR0B2) inhibits transcriptional activation of Bhmt and cystathionine γ-lyase by FOXA1, thereby controlling oscillatory homocysteine homeostasis. SHP-null mice show altered timing of expression of homocysteine metabolism genes and resistance to ethanol/homocysteine-induced hyperhomocysteinemia and glucose intolerance. SHP-null and BHMT-null mouse models, RNA-seq, ChIP assays, metabolomics Gastroenterology High 25701738
2018 AhR and SHP (NR0B2) regulate phosphatidylcholine and S-adenosylmethionine levels by controlling Pemt and Gnmt expression. Insulin/PKB signaling translocates AhR to the nucleus to induce these genes in the early fed state, while FGF15 signaling-activated SHP blocks this induction in the late fed state. SHP-null and FGF15-null mice, adenoviral expression, ChIP assays, metabolomics Nature communications High 29416063
2016 A small molecule (DSHN) activates SHP (NR0B2) by transcriptionally upregulating Shp mRNA and stabilizing SHP protein by preventing ubiquitination and degradation. Activated SHP represses Ccl2 expression by inhibiting p65-mediated CCL2 promoter activity, thereby inhibiting HCC cell migration. Small molecule microarray binding assay, RNA-seq, luciferase reporter assays, SHP overexpression/knockdown, ubiquitination assay, Shp-/- mice Molecular cancer therapeutics High 27486225
2014 SHP (NR0B2) is recruited by NF-κB p65 and forms a SHP/NF-κB p65 complex that binds the PDCD5 gene promoter, activating PDCD5 expression and triggering apoptosis via increased Bax and cytochrome C release in breast cancer cells. ChIP-on-chip, ChIP assay, luciferase reporter assay, knockdown/overexpression of SHP and PDCD5, apoptosis assays Apoptosis Medium 24343129
2004 A novel missense variant G93D in NR0B2 (SHP) shows reduced in vitro inhibition of HNF-4α transactivation of the HNF-1α promoter in MIN6-m9 and HepG2 cells, establishing that Gly-93 is functionally important for SHP's corepressor activity. SSCP/heteroduplex mutation screening, transfection reporter assays in MIN6-m9 and HepG2 cells Human mutation Medium 15459958
2018 ChREBP, rather than SHP (NR0B2), is the primary regulator of hepatic MTTP expression and VLDL secretion under normal conditions. Shp-/- mice show similar Mttp mRNA, protein, and VLDL secretion to wild-type, while Chrebp-/-Shp-/- and Chrebp-/- mice show markedly lower levels, demonstrating genetic epistasis. Shp-/- and Chrebp-/- single and double knockout mice, adenoviral overexpression in primary hepatocytes, VLDL secretion assays, promoter reporter assays Nutrients Medium 29518948

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. The Journal of clinical investigation 1125 15146238
2003 The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends in biochemical sciences 1014 12826400
1999 Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Developmental biology 430 10364425
2004 The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 393 15521018
1997 Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 380 9244303
2009 SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunological reviews 299 19290938
2000 Divergent roles of SHP-2 in ERK activation by leptin receptors. The Journal of biological chemistry 289 11085989
1999 Shp-2 tyrosine phosphatase: signaling one cell or many. Experimental cell research 245 10579910
2003 The function of the protein tyrosine phosphatase SHP-1 in cancer. Gene 237 12657462
2006 SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity 206 17157040
2010 Role of nuclear receptor SHP in metabolism and cancer. Biochimica et biophysica acta 196 20970497
2006 Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. Molecular and cellular biology 174 16354697
2005 Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nature structural & molecular biology 173 15723037
2005 A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. Cellular signalling 144 16084691
1997 Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase. The Journal of biological chemistry 141 9261115
2020 Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Communications biology 140 32184441
2000 The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions. Cell research 137 11191350
2002 Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP. Journal of lipid research 130 11907135
2007 Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome. Neuron 126 17442246
1999 SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity. The Journal of biological chemistry 121 10488096
2005 Transcriptional corepression by SHP: molecular mechanisms and physiological consequences. Trends in endocrinology and metabolism: TEM 117 16275121
2000 The protein tyrosine phosphatase Shp-2 regulates RhoA activity. Current biology : CB 116 11114521
2006 The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. Nature medicine 112 16617349
2002 Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. The Journal of biological chemistry 111 12324453
2002 Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response. Biochimica et biophysica acta 109 12421673
1998 Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner). Molecular endocrinology (Baltimore, Md.) 106 9773978
2010 Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis. The Journal of clinical investigation 105 21123943
2000 Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Molecular and cellular biology 104 10594032
2013 SHP-1 phosphatase activity counteracts increased T cell receptor affinity. The Journal of clinical investigation 101 23391724
1998 Structural determinants of SHP-2 function and specificity in Xenopus mesoderm induction. Molecular and cellular biology 99 9418864
2001 Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. Blood 97 11159516
2005 Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP. The EMBO journal 95 15933714
1999 Regulation of acidification and apoptosis by SHP-1 and Bcl-2. The Journal of biological chemistry 95 10506221
2004 SHP-2 and myeloid malignancies. Current opinion in hematology 93 14676626
2003 Identification of Shp-2 as a Stat5A phosphatase. The Journal of biological chemistry 93 12615921
1998 Regulation of angiotensin II-induced JAK2 tyrosine phosphorylation: roles of SHP-1 and SHP-2. The American journal of physiology 92 9814969
1998 Growth hormone regulation of SIRP and SHP-2 tyrosyl phosphorylation and association. The Journal of biological chemistry 79 9507023
2011 SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. The Journal of clinical investigation 75 21393858
2002 Gab1 and SHP-2 promote Ras/MAPK regulation of epidermal growth and differentiation. The Journal of cell biology 75 12370245
2022 SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses. Nature immunology 71 36581713
2018 SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression. Cancer research 71 29776962
2001 Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP. Biochemistry 70 11735420
2009 Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype. Laboratory investigation; a journal of technical methods and pathology 68 19398961
2009 Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B cell tolerance. Journal of immunology (Baltimore, Md. : 1950) 67 19380785
2011 Myelin suppresses axon regeneration by PIR-B/SHP-mediated inhibition of Trk activity. The EMBO journal 66 21364532
1997 Downregulated expression of SHP-1 in Burkitt lymphomas and germinal center B lymphocytes. The Journal of experimental medicine 62 9348315
2020 Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A. Nature communications 61 33235221
2011 SHP-1 in cell-cycle regulation. Anti-cancer agents in medicinal chemistry 61 21291405
2005 Heme transfer from streptococcal cell surface protein Shp to HtsA of transporter HtsABC. Infection and immunity 60 16041024
2002 SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC. Blood 59 12176909
2000 The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin. The Journal of biological chemistry 58 10835420
2006 Sequence specificity of SHP-1 and SHP-2 Src homology 2 domains. Critical roles of residues beyond the pY+3 position. The Journal of biological chemistry 56 16702225
2018 AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle. Nature communications 53 29416063
2018 Large-Scale Phosphoproteomics Reveals Shp-2 Phosphatase-Dependent Regulators of Pdgf Receptor Signaling. Cell reports 52 29514104
2016 A Novel Small Molecule Activator of Nuclear Receptor SHP Inhibits HCC Cell Migration via Suppressing Ccl2. Molecular cancer therapeutics 50 27486225
2018 SHP-1 regulates hematopoietic stem cell quiescence by coordinating TGF-β signaling. The Journal of experimental medicine 49 29669741
2010 Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation. Nucleic acids research 49 20375098
2015 Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice. Gastroenterology 48 25701738
2017 Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy. International journal of molecular sciences 47 28594363
2019 SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling. Frontiers in immunology 46 31708921
2009 Nuclear receptor SHP activates miR-206 expression via a cascade dual inhibitory mechanism. PloS one 44 19721712
2010 Novel polymorphisms of nuclear receptor SHP associated with functional and structural changes. The Journal of biological chemistry 42 20516075
1999 Immune signalling: SHP-2 docks at multiple ports. Current biology : CB 40 10074424
2012 Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1. Circulation research 39 22415018
2013 Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice. Molecular and cellular biology 37 23530062
2010 Deficient SOCS3 and SHP-1 expression in psoriatic T cells. The Journal of investigative dermatology 37 20130595
2009 SHP-2 expression negatively regulates NK cell function. Journal of immunology (Baltimore, Md. : 1950) 37 19915046
1999 Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins. Journal of neurochemistry 37 10098842
2010 Farnesoid X receptor activation mediates head-to-tail chromatin looping in the Nr0b2 gene encoding small heterodimer partner. Molecular endocrinology (Baltimore, Md.) 36 20444884
2004 FLT3/ITD mutation signaling includes suppression of SHP-1. The Journal of biological chemistry 36 15574429
2023 Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. European journal of pharmacology 35 37263401
2023 Targeting pathogenic macrophages by the application of SHP-1 agonists reduces inflammation and alleviates pulmonary fibrosis. Cell death & disease 35 37291088
2021 Luteolin alleviates ulcerative colitis through SHP-1/STAT3 pathway. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 35 34014331
2006 SHP-1 inhibits LPS-mediated TNF and iNOS production in murine macrophages. Biochemical and biophysical research communications 35 16487932
2013 Expression and clinical significance of tyrosine phosphatase SHP-2 in colon cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 32 24439672
2011 Nuclear receptor SHP inhibition of Dnmt1 expression via ERRγ. FEBS letters 32 21459093
2010 Overexpression of nuclear receptor SHP in adipose tissues affects diet-induced obesity and adaptive thermogenesis. American journal of physiology. Endocrinology and metabolism 32 20124506
2005 RNA interference targeting SHP-1 attenuates myocardial infarction in rats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 16223786
2019 Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2-mediated signaling. Neuro-oncology 31 31232447
2023 Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals. Oncology research 30 37304233
2019 Regulation of peripheral and central immunity: Understanding the role of Src homology 2 domain-containing tyrosine phosphatases, SHP-1 & SHP-2. Immunobiology 30 31561841
2016 Ginkgetin Blocks Constitutive STAT3 Activation and Induces Apoptosis through Induction of SHP-1 and PTEN Tyrosine Phosphatases. Phytotherapy research : PTR 30 27059688
2021 Dynamic variability in SHP-1 abundance determines natural killer cell responsiveness. Science signaling 29 34752140
2016 Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1. Nature communications 29 27670070
2011 Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease. The Journal of steroid biochemistry and molecular biology 28 21550402
2010 The orphan nuclear receptor SHP is a positive regulator of osteoblastic bone formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 28 19594294
2012 The tyrosine phosphatase SHP-1 dampens murine Th17 development. Blood 27 22438258
2008 A critical role of SHP-1 in regulation of type 2 inflammation in the lung. American journal of respiratory cell and molecular biology 27 18952567
2013 Structural insights into gene repression by the orphan nuclear receptor SHP. Proceedings of the National Academy of Sciences of the United States of America 26 24379397
2003 Gab1, SHP-2 and other novel regulators of Ras: targets for anticancer drug discovery? Current cancer drug targets 26 12769687
2019 Inactivation of the tyrosine phosphatase SHP-2 drives vascular dysfunction in Sepsis. EBioMedicine 25 30905847
2014 RFX1-dependent activation of SHP-1 induces autophagy by a novel obatoclax derivative in hepatocellular carcinoma cells. Oncotarget 25 24952874
2014 NF-κB p65 recruited SHP regulates PDCD5-mediated apoptosis in cancer cells. Apoptosis : an international journal on programmed cell death 24 24343129
2022 SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2. Oncogene 23 35034964
2018 ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion. Nutrients 23 29518948
2017 Crocin Suppresses Constitutively Active STAT3 Through Induction of Protein Tyrosine Phosphatase SHP-1. Journal of cellular biochemistry 23 28295507
2016 Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity. JCI insight 23 27812544
2001 SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis. Journal of cell science 23 11493654
2020 Regulation of autoimmune arthritis by the SHP-1 tyrosine phosphatase. Arthritis research & therapy 22 32586377
2004 Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity. Human mutation 22 15459958