Affinage

TPO

Thyroid peroxidase · UniProt P07202

Length
933 aa
Mass
103.0 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The TPO symbol in this corpus resolves to two molecularly distinct, internally coherent proteins, and the synthesis here treats them separately. Thyroid peroxidase is a heme-containing, calcium-binding enzyme on the apical membrane of thyrocytes that catalyzes iodide organification, the essential committed step of thyroid hormone synthesis (PMID:20153806). Cryo-EM of its extracellular domain resolves a monomeric four-domain architecture (N-terminal, peroxidase/POD, CCP-like, and EGF-like domains) in which a Cys146–Cys756 disulfide locks domain orientation, and which positions the heme, calcium site, and active-site entrance on the face opposite the POD-domain autoantibody epitopes (PMID:36537574). Catalysis depends on a distal His239 and a proximal His494, with Asn579 stabilizing the proximal histidine—loss of these residues in the alternatively spliced TPO-2 form abolishes activity (PMID:9510129). Inactivating TPO mutations cause thyroid dyshormonogenesis and congenital hypothyroidism with a total iodide organification defect, and residual in vitro enzymatic activity quantitatively tracks clinical severity (PMID:20153806, PMID:32088313). Separately, thrombopoietin is a hematopoietic cytokine that signals through the receptor c-Mpl to control megakaryocyte number, polyploidization, and platelet production, as well as hematopoietic stem cell self-renewal (PMID:9474742). Ligand engagement activates JAK2 (but not JAK1) and the STAT5/STAT3, PI3K/Akt, and Ras/MAPK arms (PMID:7544303, PMID:7545904, PMID:8639823), with receptor tyrosine Y112 recruiting Gab1/Gab2 to drive PI3K/Akt and proliferation (PMID:11402314), and the adaptor Lnk acting through its SH2 domain as a negative regulator of these outputs (PMID:15337790). The balance between proliferation and differentiation is set by the relative levels of JAK2 and MPL protein and by opposing MEK/ERK versus PI3K/Akt/mTOR control of ploidy (PMID:16449323, PMID:25143485).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 High

    Establishing the immediate signaling output of thrombopoietin defined how c-Mpl engagement is transduced, showing it activates the JAK-STAT axis and selectively engages JAK2 rather than JAK1.

    Evidence EMSA, tyrosine phosphorylation and immunoprecipitation assays in hematopoietic and myeloid precursor cells, including a JAK1 negative control distinguishing TPO from IL-3

    PMID:7544303 PMID:7545904

    Open questions at the time
    • Does not resolve which STAT outputs drive proliferation versus differentiation
    • Direct receptor residues coupling c-Mpl to JAK2 not mapped here
  2. 1996 Medium

    Identification of a TPO-dependent megakaryoblastic cell line and the Grb2/JAK2/c-Cbl complex clarified how the receptor nucleates downstream adaptors distinct from receptor tyrosine kinase signaling.

    Evidence JAK2/STAT5 phosphorylation in UT-7/TPO cells and Co-IP comparing TPO/c-Mpl versus SCF/c-Kit adaptor recruitment

    PMID:8639823 PMID:8950973

    Open questions at the time
    • Functional consequence of the Grb2/JAK2 complex on cell fate not isolated
    • c-Cbl downstream role undefined
  3. 1998 High

    Genetic ablation of TPO and c-Mpl established the physiological role of the cytokine as a controller of megakaryocyte/platelet number and a regulator of HSC repopulation, with a platelet-mass feedback loop.

    Evidence TPO and c-Mpl knockout mice with platelet counts, progenitor enumeration, BM repopulation assays, and platelet receptor-binding analysis

    PMID:9474742

    Open questions at the time
    • Molecular basis of HSC self-renewal effect not defined here
    • Does not explain ploidy control mechanism
  4. 1998 Medium

    Assigning the catalytic residues of thyroid peroxidase and correlating them with the inactive splice variant explained the structural requirements for peroxidase activity.

    Evidence Sequence alignment with myeloperoxidase identifying His239/His494/Asn579/Arg396 plus functional correlation with activity-null TPO-2 lacking residues 533–589

    PMID:9510129

    Open questions at the time
    • No direct site-directed mutagenesis of individual residues reported
    • Compound I formation role of Arg396 inferred by analogy
  5. 2001 High

    Mapping c-Mpl Y112 to Gab1/Gab2 recruitment defined the receptor module that couples thrombopoietin to PI3K/Akt and proliferation.

    Evidence Co-IP of Gab1/2 with Shc/SHP2/PI3K/Grb2 and Y112 mutant c-Mpl analysis in UT7 and primary megakaryocytic progenitors

    PMID:11402314

    Open questions at the time
    • Why only Gab1 is expressed in primary progenitors not explained
    • Quantitative contribution of PI3K versus other arms to proliferation not partitioned
  6. 2002 Medium

    Identifying PLZF/GATA1 control of the TpoR promoter showed how receptor expression itself is transcriptionally set during megakaryocytic commitment.

    Evidence Promoter deletion mapping and PLZF/GATA1 Co-IP in retrovirally transduced TF1 cells

    PMID:12242665

    Open questions at the time
    • Direct DNA-binding stoichiometry of the PLZF/GATA1 complex not resolved
    • In vivo relevance to receptor levels not tested
  7. 2003 High

    Dissection of the MAPK branch separated essential from dispensable kinases, showing Raf-1 is not required while p38 links TPO to Hoxb4 via USF-1 for HSC self-renewal.

    Evidence raf-1 knockout mice with ERK readouts and p38-inhibitor/USF-1 induction analysis with tpo-/- HSC comparison

    PMID:12855555 PMID:14576068

    Open questions at the time
    • Which Raf isoform substitutes for Raf-1 in ERK activation not identified
    • Magnitude of Hoxb4 change (2–5 fold) leaves quantitative contribution to self-renewal uncertain
  8. 2005 Medium

    Tracing c-myc induction to a PI3K/MAPK route independent of Akt/mTOR refined which downstream effectors control megakaryocyte transcriptional output.

    Evidence qRT-PCR of c-myc with PI3K/MAPK/Akt/PKCζ/mTOR inhibitors and active-Akt overexpression in UT-7, BaF3/Mpl, and primary megakaryocytes

    PMID:16380230

    Open questions at the time
    • The PI3K effector bridging to c-myc independent of Akt not identified
    • Direct transcriptional mediator at the c-myc locus undefined
  9. 2006 Medium

    Defining opposing MEK/ERK and PI3K/AKT/mTOR effects on ploidy, with cyclin D3 localization as readout, established how a single ligand balances proliferation against polyploidization.

    Evidence PD98059 and rapamycin treatment with ploidy flow cytometry and cyclin D3 immunolocalization in human CD34+-derived megakaryocytes

    PMID:16449323

    Open questions at the time
    • Mechanism linking mTOR to nuclear cyclin D3 retention not resolved
    • Single-lab pharmacology without genetic confirmation
  10. 2004 High

    Identifying Lnk as an SH2-dependent negative regulator placed a brake on the breadth of TPO signaling outputs.

    Evidence Lnk overexpression and knockout mice with STAT3/STAT5/Akt/MAPK phosphorylation, domain-deletion mutants, and megakaryocyte colony assays

    PMID:15337790

    Open questions at the time
    • The phosphotyrosine docking site engaged by the Lnk SH2 domain not mapped
    • PH domain contribution mechanism unresolved
  11. 2010 High

    Consolidating TPO genetics fixed thyroid peroxidase as the enzyme whose loss causes a total iodide organification defect and congenital hypothyroidism.

    Evidence Functional/genetic analysis of TPO mutations across congenital hypothyroidism cohorts (review of 61 mutations)

    PMID:20153806

    Open questions at the time
    • Per-residue structural consequences not yet linked to mechanism at this stage
    • Genotype-phenotype quantitation not established here
  12. 2014 High

    Showing that JAK2 and MPL protein levels dictate proliferation-versus-differentiation outcome revealed a dosage logic, including a paradoxical pro-megakaryocytic effect of low-dose JAK2 inhibition.

    Evidence siRNA knockdown of JAK2/MPL, JAK2 chemical inhibition, in vitro/in vivo differentiation assays, and patient-sample Western blots

    PMID:25143485

    Open questions at the time
    • Quantitative thresholds of JAK2/MPL setting each fate not defined
    • How the same kinase output is interpreted as opposite fates remains unresolved
  13. 2015 Medium

    Demonstrating that thrombopoietin drives metabolic reprogramming in colorectal tumor-initiating cells extended its signaling into oncogenic self-renewal beyond hematopoiesis.

    Evidence Metabolic profiling, acetylation/Wnt/redox assays, c-myc loss-of-function in CD110+ TICs and in vivo liver metastasis models

    PMID:26140605

    Open questions at the time
    • Generality across cancer types not established
    • Direct receptor coupling to lysine degradation enzymes not mapped
  14. 2018 Medium

    Identifying breast-expressed thyroid peroxidase and its predominantly cytoplasmic distribution showed enzymatic activity depends on apical/cell-surface presentation absent in mammary cells.

    Evidence Western blot, glycosylation analysis, isoelectric focusing, peroxidase activity assays, and subcellular localization in breast-derived cell lines

    PMID:29513734

    Open questions at the time
    • Functional role of cytoplasmic breast TPO undefined
    • Trafficking defect mechanism not identified
  15. 2018 Medium

    Linking thyroid TPO downregulation to a p38/TRHr pathway revealed an environmental-chemical route by which TPO expression is suppressed.

    Evidence Rat triclosan exposure with Nthy-ori 3-1 p38 inhibitor and TRHr siRNA experiments measuring TPO expression

    PMID:29462796

    Open questions at the time
    • Direct transcriptional mechanism downstream of TRHr on the TPO gene not defined
    • Generalizability beyond triclosan unknown
  16. 2020 Medium

    Showing thrombopoietin and c-Mpl expression in CNS neurons with PI3K/Akt-mediated neuroprotection extended the cytokine's anti-apoptotic signaling to a non-hematopoietic tissue.

    Evidence Human CNS immunohistochemistry, neonatal rat hypoxic-ischemic model, and PI3K/Akt and Bcl-2/BAX pathway analysis with proliferation/apoptosis assays

    PMID:32341206

    Open questions at the time
    • Physiological role of neuronal TPO under non-injury conditions unknown
    • Single-lab finding without independent confirmation
  17. 2023 High

    The first high-resolution structure of thyroid peroxidase resolved its domain architecture, the disulfide stabilizing it, and the spatial separation of catalytic site from autoantibody epitopes.

    Evidence Cryo-EM of the TPO extracellular domain at 3.4–3.92 Å complexed with two independent Fab fragments

    PMID:36537574

    Open questions at the time
    • Membrane-anchored full-length conformation not resolved
    • Catalytic cycle intermediates not captured structurally

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the same intracellular kinase modules are quantitatively interpreted to produce opposite megakaryocyte fates, and whether the non-hematopoietic thrombopoietin roles (CNS, tumor metabolism) operate through the canonical c-Mpl module.
  • No unified quantitative model linking JAK2/MPL dosage to fate
  • Receptor coupling for metabolic and neuroprotective effects not mapped
  • Structural basis of thyroid TPO catalysis at the membrane unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-109582 Hemostasis 2 R-HSA-1430728 Metabolism 2
Partners
GAB1GAB2GRB2JAK2LNKMPLSTAT3STAT5

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 Cryo-EM structures of human thyroid peroxidase (TPO) extracellular domain were determined at 3.4–3.92 Å resolution, revealing TPO as a monomer with four domains: N-terminal domain, peroxidase domain (POD), complement control protein (CCP)-like domain, and EGF-like domain. A disulfide bond between Cys146 (POD) and Cys756 (CCP) fixes the relative domain positions. The haem group, calcium binding site, and enzyme active site entrance are on the opposite face from the autoantibody binding sites (POD domain). Cryo-electron microscopy with TPO complexed with Fab fragments (monoclonal autoantibody 2G4 and mouse monoclonal 4F5) Journal of molecular endocrinology High 36537574
1998 TPO catalytic mechanism depends on distal histidine His239 and proximal histidine His494 (identified by sequence alignment with myeloperoxidase). Asn579, which likely forms a stabilizing hydrogen bond with the proximal histidine, is absent in the alternatively spliced form TPO-2, explaining the lack of enzymatic activity of TPO-2. Arg396 is proposed to be required for compound I formation by analogy with other peroxidases. Amino acid sequence alignment across mammalian and invertebrate peroxidases; functional inference from alternatively spliced variant lacking residues 533–589 Thyroid : official journal of the American Thyroid Association Medium 9510129
2010 TPO is a heme-binding protein localized on the apical membrane of the thyrocyte; its enzymatic activity is essential for thyroid hormonogenesis (iodide organification). Inactivating mutations in TPO cause thyroid dyshormonogenesis and congenital hypothyroidism with a total iodide organification defect. Genetic/functional analysis of TPO mutations in congenital hypothyroidism patients; review of 61 annotated mutations Molecular and cellular endocrinology High 20153806
2020 In vitro enzyme activity assays of TPO missense mutants demonstrated that residual TPO enzymatic activity correlates with clinical severity in congenital hypothyroidism: patients with <15% residual activity had severe CH (markedly elevated TSH, pronounced goiter, higher L-thyroxine requirement), while those with >16% residual activity had mild CH. In vitro enzymatic activity assay of TPO mutants expressed in cells; correlation with clinical phenotype in 230 Chinese CH patients Molecular and cellular endocrinology High 32088313
2018 Breast-expressed TPO has slightly lower molecular weight than thyroid TPO due to decreased glycosylation. Breast TPO exhibits enzymatic activity and isoelectric point comparable to thyroid TPO, but in mammary cell lines the majority of TPO is cytoplasmic and cell-surface expression is insufficient to detect enzymatic activity. No peroxidase activity or dimer formation was detected in breast-derived cell lines. Western blot, glycosylation analysis, peroxidase activity assay, isoelectric focusing, subcellular localization in breast tissue-derived cell lines PloS one Medium 29513734
1995 TPO (thrombopoietin) induces tyrosine phosphorylation and activation of STAT5 (major component of the DNA-binding complex) and STAT3 in hematopoietic cells via its receptor c-Mpl, defining a rapid JAK-STAT signaling pathway downstream of TPO. DNA-binding assays (EMSA), tyrosine phosphorylation assays, immunoprecipitation in hematopoietic cells stimulated with TPO FEBS letters High 7544303
2004 The adaptor protein Lnk negatively regulates TPO/c-Mpl signaling. Lnk overexpression attenuates TPO-induced STAT3, STAT5, Akt, and MAPK signaling; Lnk deficiency causes enhanced and prolonged activation of these pathways in megakaryocytes. The SH2 domain of Lnk is essential for this inhibitory function; the PH domain contributes but is not essential; the conserved C-terminal tyrosine is dispensable. Overexpression and knockout mouse studies; phosphorylation assays for STAT3, STAT5, Akt, MAPK; domain-deletion mutant analysis; megakaryocyte colony assays The Journal of experimental medicine High 15337790
2001 Upon TPO stimulation, adaptor proteins Gab1 and Gab2 are tyrosine-phosphorylated and associate with Shc, SHP2, PI3-kinase, and Grb2 in mpl-expressing cells. In primary human megakaryocytic progenitors, only Gab1 is expressed and phosphorylated. Y112 in the C-terminal cytoplasmic domain of c-Mpl is required for Gab1/2 phosphorylation and subsequent PI3K/Akt activation; a Y112 mutant mpl fails to activate PI3K and does not support cell proliferation. Co-immunoprecipitation, tyrosine phosphorylation assays, mpl mutant analysis in UT7 and primary cells Oncogene High 11402314
1995 TPO (thrombopoietin) stimulation induces tyrosine phosphorylation of JAK2, Shc, and Vav in myeloid precursor cells. JAK1 phosphorylation is induced by IL-3 but NOT by TPO, distinguishing TPO and IL-3 signal transduction at a molecular level. Tyrosine phosphorylation assays and immunoprecipitation of JAK1, JAK2, Shc, Vav in myeloid precursor cells after TPO or IL-3 stimulation Biochemical and biophysical research communications Medium 7545904
2005 TPO (thrombopoietin) induces c-myc expression in megakaryocytes through a PI3K- and MAPK-dependent pathway. This induction is not mediated by Akt, PKCζ, or mTOR, distinguishing the c-myc regulatory pathway from other PI3K downstream effectors. Quantitative real-time RT-PCR of c-myc; pharmacological inhibitors of PI3K, MAPK, Akt, PKCζ, mTOR; active Akt overexpression in UT-7 and BaF3/Mpl cells and primary murine megakaryocytes Cellular signalling Medium 16380230
2006 In TPO-driven megakaryocyte differentiation, MEK inhibition (via PD98059) increased polyploidization, while mTOR inhibition (via rapamycin) strongly inhibited polyploidization. MEK inhibition caused nuclear localization of cyclin D3, whereas mTOR inhibition caused exclusively cytoplasmic cyclin D3 localization. This demonstrates that TPO-activated MEK/ERK and PI3K/AKT/mTOR pathways have opposing effects on megakaryocyte ploidy. Pharmacological inhibition (PD98059, rapamycin), Western blot for p-ERK and p70S6K, flow cytometry for DNA content, immunolocalization of cyclin D3 in human CD34+-derived megakaryocytes Journal of cell science Medium 16449323
2014 JAK2 and MPL protein expression levels determine whether TPO induces megakaryocyte proliferation or differentiation: decreasing JAK2 or MPL expression (or JAK2 chemical inhibition) suppresses TPO-induced proliferation arrest and differentiation. Low doses of JAK2 inhibitors paradoxically increase MK production both in vitro and in vivo. siRNA knockdown of JAK2/MPL, JAK2 chemical inhibitors, in vitro megakaryocyte differentiation assays, in vivo mouse studies, Western blot for JAK2/MPL in patient samples Blood High 25143485
2003 Raf-1 is NOT required for megakaryocytopoiesis or TPO-induced ERK1/2 phosphorylation. raf-1-/- mice have normal to slightly elevated platelet counts, normal megakaryocyte expansion and ploidy, and normal TPO-induced ERK1/2 phosphorylation without compensatory upregulation of A-Raf or B-Raf. raf-1 knockout mice; platelet counts, megakaryocyte development assays, ERK1/2 phosphorylation assays, A-Raf/B-Raf expression analysis Blood High 14576068
2003 TPO (thrombopoietin) stimulates Hoxb4 expression 2–3-fold in primitive hematopoietic cell lines and HSCs via p38 MAPK, which induces upstream stimulating factor 1 (USF-1), a transcription factor that regulates Hoxb4. tpo-/- HSCs express 2–5-fold less Hoxb4 than controls, providing a molecular pathway for TPO's role in HSC self-renewal. Gene expression analysis in tpo-/- vs. wild-type HSC populations; p38 MAPK inhibitor studies; USF-1 induction assays in EML and UT-7/TPO cells Blood Medium 12855555
1998 TPO and c-Mpl knockout mice are viable but have ~90% reduction in platelet counts due to reduced megakaryocyte progenitor numbers and decreased megakaryocyte ploidy. The primary physiological role of TPO in vivo is to control the number, not the maturation, of megakaryocytes and platelets. TPO also affects hematopoietic stem cell repopulating capacity. Circulating TPO levels are regulated by the platelet mass through binding to c-Mpl receptors on platelets (feedback mechanism). Gene-targeted TPO and c-Mpl knockout mouse studies; platelet counts; BM repopulation assays; progenitor cell enumeration Stem cells (Dayton, Ohio) High 9474742
1996 TPO (thrombopoietin) induces tyrosine phosphorylation of JAK2 and STAT5-related protein in megakaryoblastic cells. The UT-7/TPO cell line established absolute TPO dependence for growth and survival, with TPO signaling through c-Mpl to activate JAK2/STAT5 pathway. Western blot for JAK2 and STAT5 tyrosine phosphorylation in UT-7/TPO cells; mpl mRNA detection by RT-PCR Blood Medium 8639823
2000 Platelets release full-length biologically active TPO (thrombopoietin) upon activation with platelet agonists. Platelet fractionation indicates stored TPO is contained in granules. Pre-incubation with TPO peptide mimetic or truncated TPO increases TPO release 3–5-fold upon activation, suggesting competition with Mpl-bound TPO. Platelet stimulation assays, platelet fractionation experiments, biological activity assays, clinical correlation with DIC patients Thrombosis and haemostasis Medium 10896250
1996 TPO (thrombopoietin) stimulation leads to formation of a Grb2 complex containing JAK2 (via c-Mpl), distinct from SCF/c-Kit stimulation where Grb2 interacts with c-Kit through its SH2 domain. TPO-induced c-Cbl tyrosine phosphorylation occurs via JAK2 (non-tyrosine kinase receptor pathway) rather than direct receptor interaction. Co-immunoprecipitation, in vitro binding assays, tyrosine phosphorylation assays in M-07e cells stimulated with TPO or SCF Oncogene Medium 8950973
2015 TPO (thrombopoietin) promotes liver metastasis of CD110+ colorectal cancer tumor-initiating cells by activating lysine degradation, generating acetyl-CoA (used for p300-dependent LRP6 acetylation triggering Wnt signaling for self-renewal) and glutamate (modulating redox status for drug resistance). TPO-mediated c-myc induction orchestrates chromatin modifier recruitment to regulate metabolic gene expression. Metabolic profiling, acetylation assays, Wnt signaling assays, redox assays, c-myc loss-of-function in CD110+ TICs; in vivo liver metastasis models Cell stem cell Medium 26140605
2020 Both TPO (thrombopoietin) and its receptor c-Mpl are expressed in neurons of the human CNS. TPO is neuroprotective in hypoxic-ischemic neonatal rat brain models, reducing brain damage. TPO promotes C17.2 cell proliferation through PI3K/Akt signaling and exerts anti-apoptotic effects via the Bcl-2/BAX pathway by suppressing mitochondrial membrane potential loss. Immunohistochemistry of human CNS tissue; neonatal rat hypoxic-ischemic model; Western blot for PI3K/Akt and Bcl-2/BAX pathway components; proliferation and apoptosis assays Aging Medium 32341206
2006 TPO (thrombopoietin) regulates PDGF-B, PDGFRα, and PDGFRβ expression in UT-7/TPO megakaryocytic cells, induces tyrosine phosphorylation of PDGFRα (but not PDGFRβ), and promotes PDGFRαβ heterodimer formation. During megakaryocytic differentiation, PDGFRs form complexes with neuropilin-1 (NRP-1), suggesting NRP-1 involvement in megakaryopoiesis. Western blot, co-immunoprecipitation, immunocytochemistry, tyrosine phosphorylation assays in UT-7/TPO cells Biochemical and biophysical research communications Medium 25744030
2018 TPO expression in thyroid cells is downregulated via a p38/TRHr-dependent pathway: triclosan activates p38, which induces TRHr expression; inhibition of p38 suppresses TRHr induction and restores TPO expression. TRHr siRNA knockdown also suppresses TPO. Rat in vivo triclosan treatment; Nthy-ori 3-1 cell culture with p38 inhibitors and TRHr siRNA; Western blot and RT-PCR for TPO expression Cellular physiology and biochemistry Medium 29462796
2006 IL-1α/IFN-γ (Th1 cytokines) downregulate TPO protein and mRNA expression in human thyrocytes in a nitric oxide (NO)-dependent manner; this effect is partially prevented by the NOS inhibitor L-NAME, establishing NO as a mediator of Th1 cytokine-induced TPO suppression. Cytokine treatment of isolated human thyrocytes; L-NAME (NOS inhibitor) co-incubation; Western blot and RT-PCR for TPO and ThOXs; NO release measurement American journal of physiology. Endocrinology and metabolism Medium 16478776
2002 PLZF activates TPO receptor (TpoR/c-Mpl) transcription in megakaryocytic cells by binding to a PLZF recognition site in the proximal TpoR promoter. PLZF and GATA1 proteins co-immunoprecipitate in PLZF-expressing cells, and their co-expression potentiates megakaryocytic marker upregulation, suggesting a PLZF/GATA1 transcriptional complex regulates TpoR expression. Promoter deletion constructs, co-immunoprecipitation of PLZF and GATA1, retroviral transduction of TF1 cells, flow cytometry for megakaryocytic markers Oncogene Medium 12242665

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer discovery 408 30093503
2004 Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. The Journal of experimental medicine 160 15337790
2015 TPO-Induced Metabolic Reprogramming Drives Liver Metastasis of Colorectal Cancer CD110+ Tumor-Initiating Cells. Cell stem cell 128 26140605
2005 The cysteine-rich secretory protein domain of Tpx-1 is related to ion channel toxins and regulates ryanodine receptor Ca2+ signaling. The Journal of biological chemistry 114 16339766
1996 Establishment and characterization of the thrombopoietin-dependent megakaryocytic cell line, UT-7/TPO. Blood 99 8639823
1999 Purification and characterization of a second type thioredoxin peroxidase (type II TPx) from Saccharomyces cerevisiae. Biochemistry 97 9888818
2003 Role of the thioredoxin system and the thiol-peroxidases Tpx and Bcp in mediating resistance to oxidative and nitrosative stress in Helicobacter pylori. Microbiology (Reading, England) 94 12576586
1998 Hematopoietic deficiencies in c-mpl and TPO knockout mice. Stem cells (Dayton, Ohio) 91 9474742
2010 Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Molecular and cellular endocrinology 89 20153806
1995 Production of thrombopoietin (TPO) by rat hepatocytes and hepatoma cell lines. Experimental hematology 86 7498368
1996 Autoantigen 1 of the guinea pig sperm acrosome is the homologue of mouse Tpx-1 and human TPX1 and is a member of the cysteine-rich secretory protein (CRISP) family. Molecular reproduction and development 85 9115720
2003 Thrombopoietin stimulates Hoxb4 expression: an explanation for the favorable effects of TPO on hematopoietic stem cells. Blood 84 12855555
2021 Thrombopoietin Receptor Agonists (TPO-RAs): Drug Class Considerations for Pharmacists. Drugs 83 34160821
1995 Thrombopoietin (TPO) induces tyrosine phosphorylation and activation of STAT5 and STAT3. FEBS letters 77 7544303
2021 TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations. Molecular cancer therapeutics 75 34158340
2019 Causal Relationship Between Anti-TPO IgE and Chronic Urticaria by In Vitro and In Vivo Tests. Allergy, asthma & immunology research 71 30479075
2008 The Campylobacter jejuni thiol peroxidases Tpx and Bcp both contribute to aerotolerance and peroxide-mediated stress resistance but have distinct substrate specificities. Journal of bacteriology 70 18515414
2001 Tpx-1 is a component of the outer dense fibers and acrosome of rat spermatozoa. Molecular reproduction and development 69 11144214
2005 Relation of anti-TPO autoantibody titre and T-lymphocyte cytokine production patterns in Hashimoto's thyroiditis. Clinical endocrinology 67 16060913
2000 Platelets release thrombopoietin (Tpo) upon activation: another regulatory loop in thrombocytopoiesis? Thrombosis and haemostasis 66 10896250
2017 Iodide handling disorders (NIS, TPO, TG, IYD). Best practice & research. Clinical endocrinology & metabolism 62 28648508
1998 Molecular cloning of the rat Tpx-1 responsible for the interaction between spermatogenic and Sertoli cells. Biochemical and biophysical research communications 62 9675100
1992 The mouse male germ cell-specific gene Tpx-1: molecular structure, mode of expression in spermatogenesis, and sequence similarity to two non-mammalian genes. Mammalian genome : official journal of the International Mammalian Genome Society 59 1638086
1999 Expression pattern, subcellular localization and structure--function relationship of rat Tpx-1, a spermatogenic cell adhesion molecule responsible for association with Sertoli cells. Development, growth & differentiation 58 10646801
2006 Inhibition of TPO-induced MEK or mTOR activity induces opposite effects on the ploidy of human differentiating megakaryocytes. Journal of cell science 55 16449323
1999 The reduction of in vitro radiation-induced Fas-related apoptosis in CD34+ progenitor cells by SCF, FLT-3 ligand, TPO, and IL-3 in combination resulted in CD34+ cell proliferation and differentiation. Stem cells (Dayton, Ohio) 55 10527462
2020 TPO antibody positivity and adverse pregnancy outcomes. Best practice & research. Clinical endocrinology & metabolism 53 32883611
1995 Genetic and epitopic analysis of thyroid peroxidase (TPO) autoantibodies: markers of the human thyroid autoimmune response. Clinical and experimental immunology 53 7544244
2015 BRAF V600E and decreased NIS and TPO expression are associated with aggressiveness of a subgroup of papillary thyroid microcarcinoma. European journal of endocrinology 51 26338373
2011 TPO receptor agonist for chronic idiopathic thrombocytopenic purpura. The Cochrane database of systematic reviews 51 21735426
2014 JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation. Blood 50 25143485
2008 Comparison of immunogenicity, protective efficacy of single and cocktail DNA vaccine of Brugia malayi abundant larval transcript (ALT-2) and thioredoxin peroxidase (TPX) in mice. Acta tropica 48 18547532
2014 Increased TRAb and/or low anti-TPO titers at diagnosis of graves' disease are associated with an increased risk of developing ophthalmopathy after onset. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 46 24554511
2002 PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein. Oncogene 46 12242665
2018 Cytotoxic and genotoxic potential of the type I photoinitiators BAPO and TPO on human oral keratinocytes and V79 fibroblasts. Dental materials : official publication of the Academy of Dental Materials 45 30340767
2006 Expression of tpo mRNA in thyroid tumors: quantitative PCR analysis and correlation with alterations of ret, Braf , ras and pax8 genes. Endocrine-related cancer 45 16728576
2021 Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC? Translational oncology 44 34365220
2019 Thrombopoietin receptor agonist (TPO-RA) treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia (ITP). Platelets 44 31146647
2009 Acute and persistent Mycobacterium tuberculosis infections depend on the thiol peroxidase TpX. PloS one 42 19340292
2006 Goitrous congenital hypothyroidism and hearing impairment associated with mutations in the TPO and SLC26A4/PDS genes. The Journal of clinical endocrinology and metabolism 39 16684826
2001 Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo). Oncogene 39 11402314
1996 Ectopic expression of murine TPO receptor (c-mpl) in mice is pathogenic and induces erythroblastic proliferation. Blood 39 8781421
1999 Thrombopoietin (Tpo) in the fetus and neonate: Tpo concentrations in preterm and term neonates, and organ distribution of Tpo and its receptor (c-mpl) during human fetal development. Early human development 38 10088990
1999 A novel mutation in the TPO gene in goitrous hypothyroid patients with iodide organification defect. Clinical endocrinology 38 10468986
1998 Endogenous TPO (eTPO) levels in health and disease: possible clues for therapeutic intervention. Stem cells (Dayton, Ohio) 38 11012188
2023 Ameliorative effects of mangiferin derivative TPX on insulin resistance via PI3K/AKT and AMPK signaling pathways in human HepG2 and HL-7702 hepatocytes. Phytomedicine : international journal of phytotherapy and phytopharmacology 37 36965373
2023 Prolonged response after TPO-RA discontinuation in primary ITP: results of a prospective multicenter study. Blood 36 36893453
2008 TPO-independent megakaryocytopoiesis. Critical reviews in oncology/hematology 36 18093840
1994 Cloning and characterisation of TPO autoantibodies using combinatorial phage display libraries. Autoimmunity 36 7524700
2018 P38/TRHr-Dependent Regulation of TPO in Thyroid Cells Contributes to the Hypothyroidism of Triclosan-Treated Rats. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33 29462796
2011 Octa-arginine mediated delivery of wild-type Lnk protein inhibits TPO-induced M-MOK megakaryoblastic leukemic cell growth by promoting apoptosis. PloS one 32 21853157
1991 Genetic linkage studies of thyroid peroxidase (TPO) gene in families with TPO deficiency. The Journal of clinical endocrinology and metabolism 32 1671388
1998 Plasma thrombopoietin (TPO) levels and expression of TPO receptor on platelets in patients with myelodysplastic syndromes. British journal of haematology 30 9858230
2011 A TPO receptor agonist, ALXN4100TPO, mitigates radiation-induced lethality and stimulates hematopoiesis in CD2F1 mice. Radiation research 29 21476857
2006 Expression of TPO and ThOXs in human thyrocytes is downregulated by IL-1alpha/IFN-gamma, an effect partially mediated by nitric oxide. American journal of physiology. Endocrinology and metabolism 29 16478776
2005 Thrombopoietin (TPO) induces c-myc expression through a PI3K- and MAPK-dependent pathway that is not mediated by Akt, PKCzeta or mTOR in TPO-dependent cell lines and primary megakaryocytes. Cellular signalling 29 16380230
2006 2-Cys Peroxiredoxin TPx-1 is involved in gametocyte development in Plasmodium berghei. Molecular and biochemical parasitology 27 16597467
1996 Discrete protein interactions with the Grb2/c-Cbl complex in SCF- and TPO-mediated myeloid cell proliferation. Oncogene 27 8950973
1999 Cellular thyroid peroxidase (TPO), unlike purified TPO and adjuvant, induces antibodies in mice that resemble autoantibodies in human autoimmune thyroid disease. The Journal of clinical endocrinology and metabolism 26 10323395
1995 Localization of TDPX1, a human homologue of the yeast thioredoxin-dependent peroxide reductase gene (TPX), to chromosome 13q12. Genomics 26 7607688
2013 Pathophysiology and management of thrombocytopenia in bone marrow failure: possible clinical applications of TPO receptor agonists in aplastic anemia and myelodysplastic syndromes. International journal of hematology 25 23690288
2020 Increased Prevalence of TG and TPO Mutations in Sudanese Children With Congenital Hypothyroidism. The Journal of clinical endocrinology and metabolism 24 31867598
2020 Thyroid peroxidase in human endometrium and placenta: a potential target for anti-TPO antibodies. Clinical and experimental medicine 23 32980989
2005 Mesenchymal stem cells support expansion of in vitro irradiated CD34(+) cells in the presence of SCF, FLT3 ligand, TPO and IL3: potential application to autologous cell therapy in accidentally irradiated victims. Radiation research 23 15966759
2000 Effects of flt-3 ligand in combination with TPO on the expansion of megakaryocytic progenitors. Cell transplantation 23 10784074
2018 Diagnostic significance of CK19, galectin-3, CD56, TPO and Ki67 expression and BRAF mutation in papillary thyroid carcinoma. Oncology letters 22 29541194
2013 The TPO/c-MPL pathway in the bone marrow may protect leukemia cells from chemotherapy in AML Patients. Pathology oncology research : POR 22 24085601
1995 TPO and IL-3 induce overlapping but distinct protein tyrosine phosphorylation in a myeloid precursor cell line. Biochemical and biophysical research communications 22 7545904
2020 The TPO mutation screening and genotype-phenotype analysis in 230 Chinese patients with congenital hypothyroidism. Molecular and cellular endocrinology 21 32088313
2019 Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells. Scientific reports 21 31852910
2016 Mutation screening of the TPO gene in a cohort of 192 Chinese patients with congenital hypothyroidism. BMJ open 21 27173810
2015 Significance of CK19, TPO, and HBME-1 expression for diagnosis of papillary thyroid carcinoma. International journal of clinical and experimental medicine 21 26064355
2013 TPO genetic variants and risk of differentiated thyroid carcinoma in two European populations. International journal of cancer 21 23754668
2003 Raf-1 is not required for megakaryocytopoiesis or TPO-induced ERK phosphorylation. Blood 21 14576068
1994 Plasma-induced graft copolymerization of HEMA onto silicone rubber and TPX film improving rabbit corneal epithelial cell attachment and growth. Biomaterials 21 8199288
2017 Cytokine changes in response to TPO receptor agonist treatment in primary immune thrombocytopenia. Cytokine 20 28142109
2012 Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors. BMC cancer 19 22967017
2018 Biochemical properties of thyroid peroxidase (TPO) expressed in human breast and mammary-derived cell lines. PloS one 18 29513734
2017 Thyroid peroxidase (TPO) expressed in thyroid and breast tissues shows similar antigenic properties. PloS one 18 28575127
2017 Novel TPO receptor agonist TA-316 contributes to platelet biogenesis from human iPS cells. Blood advances 18 29296963
2002 Lineage-specific growth factors can compensate for stem and progenitor cell deficiencies at the postprogenitor cell level: an analysis of doubly TPO- and G-CSF receptor-deficient mice. Blood 18 11986210
2000 Thrombopoietin and the TPO receptorduring platelet storage. Transfusion 17 10960526
1999 Expression of ICAM-1, B7.1 and TPO on human thyrocytes induced by IFN-alpha. Chinese medical journal 17 11593644
2022 The return of RET GateKeeper mutations? an in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046. Investigational new drugs 16 35612671
1998 The efficacy of recombinant TPO in murine And nonhuman primate models for myelosuppression and stem cell transplantation. Stem cells (Dayton, Ohio) 16 11012185
2016 TPO-RAs in pITP: description of a case series and analysis of predictive factors for response. European journal of haematology 14 27797414
1998 Thrombopoietin (TPO) knockout phenotype induced by cross-reactive antibodies against TPO following injection of mice with recombinant adenovirus encoding human TPO. Journal of immunology (Baltimore, Md. : 1950) 14 9574554
2023 TPO as an indicator of lymph node metastasis and recurrence in papillary thyroid carcinoma. Scientific reports 13 37407700
2023 The association of Treg and Th17 cells development factors and anti-TPO autoantibodies in patients with recurrent pregnancy loss. BMC research notes 13 37907956
2020 Mild TPO deficiency characterized by progressive goiter and normal serum TSH level. Endocrine 13 32078117
2020 c-Mpl and TPO expression in the human central nervous system neurons inhibits neuronal apoptosis. Aging 13 32341206
2020 Augmentation of NK Cell Proliferation and Anti-tumor Immunity by Transgenic Expression of Receptors for EPO or TPO. Molecular therapy : the journal of the American Society of Gene Therapy 13 33010232
2017 Association between TPO Asn698Thr and Thr725Pro gene polymorphisms and serum anti-TPO levels in Iranian patients with subclinical hypothyroidism. Hormones (Athens, Greece) 13 28500830
1998 Proximal and distal histidines in thyroid peroxidase: relation to the alternatively spliced form, TPO-2. Thyroid : official journal of the American Thyroid Association 13 9510129
2023 Anti-TPO IgG/Total IgE Ratio: Biomarker for Omalizumab Response Prediction in Chronic Spontaneous Urticaria. International archives of allergy and immunology 12 37557083
2020 Homology between TSH-R/Tg/TPO and Hashimoto's encephalopathy autoantigens. Frontiers in bioscience (Landmark edition) 12 31585887
2015 Platelet-derived growth factor receptors form complexes with neuropilin-1 during megakaryocytic differentiation of thrombopoietin-dependent UT-7/TPO cells. Biochemical and biophysical research communications 12 25744030
2023 Cryo-electron microscopy structures of human thyroid peroxidase (TPO) in complex with TPO antibodies. Journal of molecular endocrinology 11 36537574
2017 Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype. Journal of cellular biochemistry 11 28067429
2015 Novel genetic variants in the TPO gene cause congenital hypothyroidism. Scandinavian journal of clinical and laboratory investigation 11 26174974

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