Affinage

MPL

Thrombopoietin receptor · UniProt P40238

Length
635 aa
Mass
71.2 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MPL (c-Mpl/TpoR) is a homodimeric type I cytokine receptor that serves as the central regulator of megakaryopoiesis, thrombopoiesis, and hematopoietic stem cell (HSC) self-renewal and quiescence. Upon binding its primary ligand thrombopoietin (TPO) — or the recently identified ligand PF4 — MPL activates JAK2 and TYK2, which phosphorylate STAT1/3/5, and engages PI3K/AKT, MAPK, NF-κB, and PKC pathways to promote megakaryocyte proliferation and differentiation, while in HSCs it upregulates β1-integrin and CDK inhibitors to enforce quiescence (PMID:7543416, PMID:18371409, PMID:37883794). Receptor surface expression depends on JAK2 chaperone activity and C-mannosylation at four tryptophan residues, with trafficking occurring via both conventional ER–Golgi and unconventional autolysosomal secretory routes; after activation, c-Cbl ubiquitinates MPL at K553/K573 for dual lysosomal/proteasomal degradation, while the adaptor Lnk provides negative feedback on downstream signaling (PMID:24931576, PMID:26505790, PMID:19880496, PMID:15337790). Platelet-surface MPL clears circulating TPO to establish a feedback loop controlling megakaryocyte progenitor stimulation, and loss-of-function mutations cause congenital amegakaryocytic thrombocytopenia (CAMT) primarily through defective receptor surface trafficking (PMID:24711413, PMID:24438083). Gain-of-function transmembrane mutations (W515L/K, S505N) constitutively activate JAK-STAT signaling, and mutant calreticulin hijacks MPL by acting as a rogue chaperone that multimerizes, binds the MPL extracellular domain via lectin-dependent N-glycan interactions, and drives immature receptor to the cell surface for ligand-independent activation (PMID:31697803, PMID:30902807, PMID:29946189).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Establishing MPL as the TPO receptor and demonstrating its non-redundant role in megakaryopoiesis and a platelet-mass feedback loop for TPO clearance resolved the long-sought identity of the thrombopoietic growth factor receptor.

    Evidence c-mpl knockout mice showed 85% platelet/megakaryocyte reduction with elevated circulating TPO

    PMID:8073287

    Open questions at the time
    • Mechanism of receptor-mediated TPO clearance not defined at molecular level
    • Potential roles in non-megakaryocytic lineages not explored
  2. 1995 High

    Identification of JAK2, TYK2, and STAT1/3/5 as proximal signaling effectors downstream of TPO-activated MPL defined the core signal transduction cascade for this receptor.

    Evidence Co-IP, kinase assays, and gel-shift assays in BaF3/mMpl and factor-dependent hematopoietic cell lines

    PMID:7534285 PMID:7543416

    Open questions at the time
    • Relative contributions of JAK2 vs TYK2 unclear
    • Which STAT complexes drive specific transcriptional programs not resolved
  3. 1996 High

    Discovery that the transmembrane S498N mutation constitutively activates MPL provided the first evidence that enforced receptor dimerization/conformational change in the TM domain is sufficient for ligand-independent oncogenic signaling through SHC-Raf-MAPK and JAK-STAT.

    Evidence PCR-driven random mutagenesis with Ba/F3 factor-independence and tumorigenicity assays

    PMID:8695859

    Open questions at the time
    • Structural mechanism of TM-mediated activation not elucidated
    • In vivo myeloproliferative disease potential not tested
  4. 1996 High

    Defining GATA-1 and Ets family (Ets-1, Fli-1) cooperative binding at the MPL promoter explained its megakaryocyte-restricted expression pattern.

    Evidence Promoter deletion, EMSA, and transactivation in HEL megakaryocytic cells

    PMID:8639837

    Open questions at the time
    • In vivo chromatin accessibility and enhancer landscape not mapped
    • Contribution of additional transcription factors (e.g., PlagL2 identified later) not explored
  5. 1998 High

    Demonstrating that MPL is required for HSC self-renewal and long-term repopulation capacity expanded its role from a lineage-specific receptor to a fundamental regulator of the stem cell compartment.

    Evidence Competitive repopulation and CFU-S assays in mpl−/− mice

    PMID:9448308

    Open questions at the time
    • Whether the HSC defect is cell-autonomous vs niche-mediated not fully resolved
    • Downstream transcriptional program maintaining HSC quiescence not identified
  6. 2002 Medium

    Extending downstream pathway analysis showed MPL signaling engages PI3K-Akt-Bad (anti-apoptosis) and NF-κB in megakaryocytes, broadening the known effector network beyond JAK-STAT and MAPK.

    Evidence Factor-independence assays with W508S mutant MPL in Ba/F3 cells; IKK/NF-κB activity assays in megakaryocytic cell lines

    PMID:11967992 PMID:12145691

    Open questions at the time
    • Direct contribution of NF-κB to megakaryocyte differentiation vs proliferation not dissected genetically
    • Relative importance of PI3K vs MAPK in different cellular contexts unclear
  7. 2004 High

    Identification of Lnk as a negative regulator of TPO/c-Mpl signaling established the first feedback attenuator acting at the receptor-proximal level, explaining how signaling amplitude and duration are controlled.

    Evidence Lnk−/− mice and SH2 domain mutagenesis with signaling analysis in megakaryocytes

    PMID:15337790

    Open questions at the time
    • Precise binding site of Lnk on MPL or JAK2 not mapped
    • Relationship between Lnk and c-Cbl-mediated ubiquitination not addressed
  8. 2007 High

    Showing that MPL signaling in the osteoblastic niche enforces HSC quiescence via β1-integrin and CDK inhibitor upregulation provided the mechanistic link between TPO/MPL and niche-dependent stem cell dormancy.

    Evidence Anti-MPL antibody treatment and exogenous TPO in vivo with cell cycle analysis of LT-HSCs

    PMID:18371409

    Open questions at the time
    • Direct transcriptional targets of MPL signaling in quiescent HSCs not catalogued
    • Contribution of other niche-derived signals cooperating with TPO not separated
  9. 2009 High

    Mapping c-Cbl as the E3 ligase that ubiquitinates MPL at K553/K573 for dual lysosomal and proteasomal degradation revealed the molecular mechanism terminating receptor signaling.

    Evidence Site-directed mutagenesis, siRNA knockdown of c-Cbl, and ubiquitination assays

    PMID:19880496

    Open questions at the time
    • Whether additional E3 ligases contribute not tested
    • How ubiquitination is coordinated with Lnk-mediated negative regulation unknown
  10. 2014 High

    Multiple studies in 2014 resolved key aspects of MPL biology: JAK2 acts as a chaperone for MPL surface trafficking via both conventional and unconventional secretory pathways; CAMT mutations principally disrupt surface presentation; Mpl on megakaryocytes/platelets is dispensable for platelet production but essential as a TPO sink preventing myeloproliferation; and Mpl expression (not TPO) is required for JAK2V617F-driven MPN.

    Evidence Proximity ligation/miniSOG-CLEM for JAK2 chaperone role; systematic CAMT mutagenesis with surface expression and TPO binding; PF4-Cre conditional KO; JAK2V617F×Mpl−/− genetic epistasis

    PMID:24438083 PMID:24711413 PMID:24931576 PMID:25339357

    Open questions at the time
    • Structure of JAK2-MPL chaperone complex not solved
    • Whether unconventional autolysosomal trafficking of MPL is regulated or constitutive not known
    • Mechanism by which MPL surface density is sensed to regulate TPO clearance not defined
  11. 2015 High

    C-mannosylation at four tryptophan residues was shown to be essential for JAK-STAT signaling competence, identifying a previously unrecognized post-translational requirement for receptor activation.

    Evidence Mass spectrometry identification of C-mannosylation sites with mutagenesis and signaling assays

    PMID:26505790

    Open questions at the time
    • Whether C-mannosylation affects receptor folding, dimerization, or ligand binding specifically is not resolved
    • Enzyme(s) responsible for C-mannosylation of MPL not identified
  12. 2017 High

    The mechanism of oncogenic mutant CALR–MPL interaction was dissected: mutant CALR binds MPL's extracellular domain via lectin-dependent glycan recognition and a positively charged mutant C-terminus; CALR homomultimerization is required for MPL binding and activation; and mutant CALR acts as a rogue chaperone transporting immature, partially glycosylated MPL to the cell surface, bypassing ER quality control.

    Evidence Systematic Co-IP, domain mutagenesis of both CALR and MPL, glycan processing analysis, subcellular fractionation, Ba/F3 transformation assays across multiple studies

    PMID:29288169 PMID:29946189 PMID:30902807 PMID:31462733

    Open questions at the time
    • Structural basis of the mutant CALR–MPL complex not determined at atomic resolution
    • Why MPL is the preferential target among cytokine receptors not explained
    • Whether therapeutic disruption of the CALR–MPL interface is feasible not tested
  13. 2020 High

    Deep mutational scanning of the MPL transmembrane domain systematically catalogued all gain-of-function mutations, confirming known drivers and revealing 7 novel activating residues plus second-site modifiers of S505N.

    Evidence Saturation mutagenesis with Ba/F3 cytokine-independent growth selection

    PMID:31697803

    Open questions at the time
    • Whether novel TM mutations occur in MPN patients not confirmed clinically
    • Structural mechanism by which different TM mutations activate receptor not visualized
  14. 2023 High

    The 3.4 Å cryo-EM structure of the TPO–MPL signaling complex revealed the homodimeric activation geometry and enabled engineering of partial agonists (TPOmod) that decouple JAK/STAT from ERK/AKT signaling, driving megakaryopoiesis without HSC expansion.

    Evidence Cryo-EM structure, engineered ligand variants, in vivo functional assays, single-cell RNA-seq

    PMID:37633268

    Open questions at the time
    • Full-length receptor structure including transmembrane and intracellular domains not resolved
    • How biased agonism at the receptor translates to selective pathway activation at the molecular level not fully defined
  15. 2024 High

    PF4 was identified as a second endogenous ligand for MPL on platelets, activating JAK2-STAT3/5 and driving platelet aggregation, establishing a non-TPO activation axis with implications for VITT pathophysiology.

    Evidence Direct binding assay, phosphorylation assays, pharmacological JAK2 inhibition, platelet aggregation

    PMID:37883794

    Open questions at the time
    • PF4 binding site on MPL relative to TPO binding site not mapped
    • Whether PF4–MPL signaling is relevant in HSC or megakaryocyte biology not tested
    • Structural basis for dual ligand recognition unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length atomic structure of MPL (including transmembrane and intracellular domains), the structural basis for how different TM mutations trigger constitutive activation, how biased agonism at MPL selectively routes intracellular signaling, and why mutant CALR preferentially targets MPL among cytokine receptors.
  • Full-length MPL structure not solved
  • Mechanism of biased signaling by partial agonists at molecular level unclear
  • Selectivity of mutant CALR for MPL over other cytokine receptors unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-109582 Hemostasis 3 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 2
Partners
CALRCBLJAK2LNKPF4STAT3STAT5TYK2
Complex memberships
TPO-MPL homodimer signaling complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 MPL (c-mpl) is the receptor for thrombopoietin (TPO) and specifically regulates megakaryocytopoiesis and thrombopoiesis; c-mpl-deficient mice have 85% reduction in platelets and megakaryocytes with elevated circulating TPO, demonstrating a feedback loop where platelet mass regulates TPO levels through receptor-mediated clearance. Gene targeting / knockout mice with hematological phenotyping Science High 8073287
1995 TPO binding to c-Mpl induces rapid tyrosine phosphorylation of JAK2, Shc, and c-Mpl itself; JAK2 physically associates with c-Mpl relatively late (20–60 min) after ligand binding, suggesting JAK2 may not be the initiating kinase in the signaling cascade. Immunoprecipitation, Western blotting, co-immunoprecipitation in BaF3/mMpl cells The Journal of Biological Chemistry High 7534285
1995 Activation of MPL by TPO rapidly induces tyrosine phosphorylation of JAK2 and TYK2 (but not JAK1 or JAK3), followed by phosphorylation of STAT1, STAT3, and STAT5, and formation of specific DNA-binding complexes. In vitro kinase assays, immunoprecipitation, gel-shift assays in factor-dependent hematopoietic cell lines Experimental Hematology High 7543416
1996 A point mutation (Ser498→Asn498) in the transmembrane domain of MPL constitutively activates the receptor, conferring factor-independent growth and activating SHC-Raf-MAPK and JAK2-STAT3/STAT5 signaling pathways. Retrovirus-mediated gene transfer with PCR-driven random mutagenesis, signaling pathway analysis in Ba/F3 cells, tumorigenicity assay Blood High 8695859
1996 The MPL promoter contains binding sites for GATA-1 and Ets family proteins (Ets-1, Fli-1) that cooperatively regulate megakaryocyte-specific MPL expression; an Ets site at –15 and another downstream of the GATA motif are critical for promoter activity. Promoter deletion analysis, EMSA/in vitro binding, transactivation assays in HEL cells Blood High 8639837
1998 c-Mpl (TPO receptor) is required for hematopoietic stem cell maintenance; mpl-/- mice have 4–12-fold fewer preprogenitor cells and severely impaired long-term hematopoietic repopulating capacity, with a stem cell-intrinsic self-renewal defect. Bone marrow transplantation, CFU-S assays, competitive repopulation assays in mpl-/- mice Proceedings of the National Academy of Sciences High 9448308
2004 The adaptor protein Lnk negatively regulates TPO/c-mpl signaling through its SH2 domain; Lnk deficiency causes enhanced and prolonged TPO-induced STAT3, STAT5, Akt, and MAPK signaling in megakaryocytes, leading to increased megakaryocyte numbers and ploidy in vivo. Overexpression and loss-of-function (Lnk-/- mice), signaling assays, domain mutagenesis The Journal of Experimental Medicine High 15337790
2004 AMG531, a recombinant Fc-linked Mpl-binding protein, competes with TPO for binding to Mpl on BaF3-Mpl cells and platelets, and induces rapid tyrosine phosphorylation of Mpl, JAK2, and STAT5. Competitive radioligand binding assay (125I-TPO), phosphorylation assays, in vitro megakaryocyte culture Cytokine Medium 14693160
2007 THPO/MPL signaling in the osteoblastic niche regulates HSC quiescence; MPL+ LT-HSCs are associated with THPO-producing osteoblasts, and MPL signaling upregulates β1-integrin and CDK inhibitors; anti-MPL antibody reduces quiescent LT-HSCs and enables HSC engraftment without irradiation. Anti-MPL neutralizing antibody treatment, exogenous THPO administration, flow cytometry, cell cycle analysis in vivo Cell Stem Cell High 18371409
2009 After TPO stimulation, c-Mpl is ubiquitinated on two intracellular lysine residues (K553 and K573) by the E3 ubiquitin ligase c-Cbl, and degraded by both lysosomal and proteasomal pathways; mutation of these lysines reduces ubiquitination, degradation, and causes hyperproliferation. Site-directed mutagenesis, siRNA knockdown, dominant-negative overexpression, ubiquitination assays Blood High 19880496
2002 A novel MPL mutation (W508S) in the intracellular domain constitutively activates three signaling pathways: SHC-Ras-Raf-MAPK/JNK, JAK-STAT, and PI3K-Akt-Bad, conferring factor-independent growth. Ba/F3 cell factor-independence assay, signaling pathway analysis Leukemia Medium 12145691
2002 MPL receptor signaling through Mpl ligand activates IKK transiently then suppresses its activity; proliferating megakaryocytes display constitutive NF-κB (p50 homodimer and p50-p65 heterodimer) DNA-binding activity that is reduced upon TPO-induced differentiation. IKK activity assays, EMSA, NF-κB reporter assay in megakaryocytic cell lines Journal of Cellular Biochemistry Medium 11967992
2006 JAK2 acts as a chaperone for Mpl, responsible for its cell-surface expression; there is a reciprocal relationship between JAK2 V617F allele burden and platelet Mpl expression in myeloproliferative disorder patients. Quantitative allele analysis and flow cytometry of patient samples; mechanistic chaperone function inferred from clinical correlates Blood Medium 16912229
2012 Wild-type MPL expression promotes RUNX1-ETO AML via PI3K/AKT (but not ERK/MEK) signaling pathway activation, which mediates the antiapoptotic function of MPL in leukemic cells. shRNA knockdown, pharmacological inhibition, signaling pathway analysis in AML cell lines and mouse models Blood Medium 22613795
2014 Mpl expression (but not TPO ligand) is required for JAK2V617F-driven MPN development; loss of Mpl significantly reduces thrombocythemia, neutrophilia, splenomegaly, and the neoplastic stem cell pool in JAK2V617F transgenic mice. Genetic epistasis: JAK2V617F transgenic x Mpl-/- and Tpo-/- mice, flow cytometry, hematological analysis Blood High 25339357
2014 Mpl expression on megakaryocytes and platelets is dispensable for platelet production but essential to prevent myeloproliferation; Mpl on megakaryocytes/platelets restricts available TPO, thereby controlling megakaryocyte progenitor stimulation. Conditional knockout (PF4-Cre), hematological and progenitor analysis, gene expression profiling Proceedings of the National Academy of Sciences High 24711413
2014 CAMT-associated mutations in c-Mpl principally cause defective receptor presentation on the cell surface; one mutant (F104S) reaches the surface but shows defective TPO binding; residues in the membrane-distal CRM Domain 1 E-F and A-B loops and Domain 2 F'-G' loop are key TPO-binding determinants. Cell surface expression assays, TPO binding assays, mutagenesis of c-Mpl ectodomain Growth Factors High 24438083
2014 Mpl traffics to the cell surface via both conventional ER-Golgi and unconventional autolysosomal secretory pathways; JAK2 acts as a chaperone for Mpl—siRNA knockdown of Jak2 causes Mpl trapping in the ER; Mpl associates with Jak2 on both intracellular and plasma membranes. Proximity ligation assay, siRNA knockdown, correlated light and electron microscopy (miniSOG fusion), surface biotinylation Traffic High 24931576
2014 c-Mpl tyrosine Y591 is phosphorylated upon TPO stimulation; its mutation to Phe reduces total receptor phosphorylation; phospho-Y591 recruits SHP-1, SYK, and BTK, with SYK mediating ERK1/2 phosphorylation downstream of Y591. Site-directed mutagenesis, SH2/PTB domain binding microarray, siRNA knockdown, phosphorylation assays Experimental Hematology Medium 24607955
2015 c-Mpl is C-mannosylated at Trp269, Trp272, Trp474, and Trp477; C-mannosylation at these four sites is essential for c-Mpl-mediated JAK-STAT signaling, as C-mannosylation-defective mutants lose signaling capacity. Mass spectrometry identification of C-mannosylation sites, site-directed mutagenesis, signaling assays Biochemical and Biophysical Research Communications High 26505790
2017 Mutant CALR binds to the extracellular domain of MPL; this interaction requires lectin-dependent CALR function and requires a positive electrostatic charge in the mutant C-terminus; three tyrosine residues in the intracellular domain of MPL are required for downstream JAK-STAT signaling activation; binding alone is insufficient for cytokine-independent growth. Co-immunoprecipitation, domain mutagenesis, hematopoietic transformation assays Blood High 29288169
2018 Mutant CALR forms homomultimers via its C-terminal frameshift-derived domain; homomultimerization is required for MPL binding and activation; disrupting intermolecular CALR interactions abolishes oncogenic MPL activation. Co-immunoprecipitation, competition assay, Ba/F3 transformation assay Leukemia High 29946189
2019 Mutant CALR acts as a rogue chaperone for TpoR/MPL, stabilizing a dimeric state and transporting partially immature TpoR (with incompletely processed N117 glycans) to the cell surface bypassing quality control; this requires TpoR N-glycosylation and a hydrophobic patch in its extracellular domain; full MPL activation requires cell-surface localization. Glycan analysis, subcellular fractionation, surface expression assays, mutagenesis, thermal stability assays, oncogenic transformation assays Blood High 30902807
2019 Mutant CALR interacts with MPL in the secretory pathway (Golgi apparatus) and on the cell surface; MPL activation by mutant CALR requires entrance into the secretion pathway and N-glycan interaction; surface localization of MPL is required for sustained downstream signaling even though initial activation occurs before cell surface. Subcellular localization assays, intracellular trafficking inhibitors, trypsin surface removal, signaling assays Leukemia High 31462733
2015 TPO promotes liver metastasis of CD110+ (MPL+) colorectal cancer tumor-initiating cells by activating lysine degradation; lysine catabolism generates acetyl-CoA for p300-dependent LRP6 acetylation leading to Wnt/self-renewal signaling, and glutamate to modulate redox status; TPO-mediated c-myc induction orchestrates metabolic gene expression via chromatin modifier recruitment. Metabolic assays, ChIP, co-IP, mutagenesis, mouse metastasis models Cell Stem Cell Medium 26140605
2020 Deep mutational scanning of the MPL transmembrane domain identified all known driver mutations (W515L/K/R/A, S505N) plus 7 novel constitutively activating mutations conferring cytokine-independent growth, and numerous second-site modifiers that enhance S505N-driven activation. Deep mutational scanning, Ba/F3 cytokine-independent growth assay Blood High 31697803
2023 Cryo-EM structure of the TPO-MPL extracellular signaling complex at 3.4 Å reveals the basis for homodimeric MPL activation; structure-guided TPO variants (TPOmod) with partial agonism decouple JAK/STAT from ERK/AKT/CREB signaling, driving megakaryopoiesis without significant HSC expansion. Cryo-EM structure determination, engineered ligand variants, in vitro and in vivo functional assays, single-cell RNA sequencing Cell High 37633268
1998 TPO stimulates PKC alpha and beta isoform activation (membrane translocation) in c-Mpl-expressing cells; PKC activation mediates TPO's mitogenic action but is not required for TPO-induced megakaryocytic differentiation marker expression. PKC translocation assay, pharmacological inhibitor (GF109203X), PKC downregulation by phorbol ester, Western blot Blood Medium 9446641
2024 PF4 (platelet factor 4) binds and activates c-Mpl on platelets, leading to JAK2 activation and STAT3/STAT5 phosphorylation, resulting in platelet aggregation; inhibition of the c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4 and VITT sera. Direct binding assay, phosphorylation assays, pharmacological inhibition, platelet aggregation assay Blood High 37883794
2016 MPL R102P mutation causes incomplete trafficking defect to the cell surface; low but not absent MPL surface expression on immature megakaryocyte progenitors allows THPO-dependent proliferative response, while defective TPO clearance by mature cells with no surface MPL leads to high circulating TPO and paradoxical thrombocytosis. Flow cytometry, [125I]-THPO binding, retroviral mouse model, CD34+ cell transduction Blood High 28034873
2011 The transcription factor PlagL2 activates Mpl transcription via two consensus sites in the proximal Mpl promoter; PlagL2-expressing leukemic cells show hyperactivation of JAK2, STAT5, Akt, and Erk1/2 in response to THPO. Promoter reporter assay, ChIP-like binding analysis, signaling pathway analysis, mouse leukemia model Leukemia Medium 21263445

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell stem cell 599 18371409
1994 Thrombocytopenia in c-mpl-deficient mice. Science (New York, N.Y.) 575 8073287
2014 CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 433 24402162
1998 Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proceedings of the National Academy of Sciences of the United States of America 322 9448308
2014 Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 310 24986690
1995 The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood 275 7529061
1996 Low levels of erythroid and myeloid progenitors in thrombopoietin-and c-mpl-deficient mice. Blood 233 8704234
2015 Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood 220 26423830
1995 The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl. The Journal of biological chemistry 207 7534285
2008 Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood 180 18519816
1996 A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation. Blood 176 8695786
2003 Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert review of vaccines 171 12899573
1995 The thrombopoietin receptor c-MPL activates JAK2 and TYK2 tyrosine kinases. Experimental hematology 163 7543416
1997 Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia. Blood 161 9354672
2004 AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine 160 14693160
2004 Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. The Journal of experimental medicine 160 15337790
2015 Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients. Blood 145 26450985
1996 Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes. Blood 130 8639837
2015 TPO-Induced Metabolic Reprogramming Drives Liver Metastasis of Colorectal Cancer CD110+ Tumor-Initiating Cells. Cell stem cell 128 26140605
2012 Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. Genes, chromosomes & cancer 123 22489043
2007 Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. British journal of haematology 122 17408465
2014 Mpl expression on megakaryocytes and platelets is dispensable for thrombopoiesis but essential to prevent myeloproliferation. Proceedings of the National Academy of Sciences of the United States of America 103 24711413
2004 Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis. Proceedings of the National Academy of Sciences of the United States of America 96 15269348
1996 Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis. Blood 94 8839850
1993 Expression of the c-mpl proto-oncogene in human hematologic malignancies. Blood 93 8393355
1998 Hematopoietic deficiencies in c-mpl and TPO knockout mice. Stem cells (Dayton, Ohio) 90 9474742
2019 Calreticulin mutants as oncogenic rogue chaperones for TpoR and traffic-defective pathogenic TpoR mutants. Blood 88 30902807
2008 JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia 85 18754026
2010 The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms. Blood 81 20304805
2006 Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2 V617F and Mpl expression. Blood 81 16912229
2017 Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. Blood 79 29288169
2009 Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood 76 19880496
1996 Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer. Blood 75 8695859
2014 The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm. Blood 68 25339357
2008 JAK and MPL mutations in myeloid malignancies. Leukemia & lymphoma 64 18297515
2018 Homomultimerization of mutant calreticulin is a prerequisite for MPL binding and activation. Leukemia 56 29946189
2006 Isolation and characterization of human myeloid progenitor populations--TpoR as discriminator between common myeloid and megakaryocyte/erythroid progenitors. Experimental hematology 56 16647566
2014 JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation. Blood 50 25143485
2011 Primary myelofibrosis with or without mutant MPL: comparison of survival and clinical features involving 603 patients. Leukemia 48 21691276
2015 C-Mannosylation of thrombopoietin receptor (c-Mpl) regulates thrombopoietin-dependent JAK-STAT signaling. Biochemical and biophysical research communications 47 26505790
2007 Dual role of Mpl receptor during the establishment of definitive hematopoiesis. Development (Cambridge, England) 47 17634189
2019 Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface. Leukemia 46 31462733
2013 Congenital amegakaryocytic thrombocytopenia iPS cells exhibit defective MPL-mediated signaling. The Journal of clinical investigation 46 23908116
2012 Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling. Blood 46 22613795
2014 Mpl traffics to the cell surface through conventional and unconventional routes. Traffic (Copenhagen, Denmark) 44 24931576
2012 The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO. Blood 44 22337712
1996 Proto-oncogene c-mpl is involved in spontaneous megakaryocytopoiesis in myeloproliferative disorders. British journal of haematology 44 8562412
2016 MPL expression on AML blasts predicts peripheral blood neutropenia and thrombocytopenia. Blood 42 27574191
2020 Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning. Blood 41 31697803
2013 Detection of MPL mutations by a novel allele-specific PCR-based strategy. The Journal of molecular diagnostics : JMD 41 23994117
2011 TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Annals of hematology 41 21904853
2008 Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1. Journal of cellular and molecular medicine 41 19175693
2017 Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis. Frontiers in endocrinology 39 28955303
2011 The thrombopoietin/MPL pathway in hematopoiesis and leukemogenesis. Journal of cellular biochemistry 39 21360575
2003 Development of a leishmaniasis vaccine: the importance of MPL. Expert review of vaccines 39 12899575
1998 Protein kinase C mediates the mitogenic action of thrombopoietin in c-Mpl-expressing UT-7 cells. Blood 39 9446641
2009 CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells. Biochemical and biophysical research communications 38 19341705
2018 MPL and CpG combination adjuvants promote homologous and heterosubtypic cross protection of inactivated split influenza virus vaccine. Antiviral research 37 29885376
2024 PF4 activates the c-Mpl-Jak2 pathway in platelets. Blood 34 37883794
2018 JAK2V617F Megakaryocytes Promote Hematopoietic Stem/Progenitor Cell Expansion in Mice Through Thrombopoietin/MPL Signaling. Stem cells (Dayton, Ohio) 32 30005133
2011 MPL mutation profile in JAK2 mutation-negative patients with myeloproliferative disorders. Diagnostic molecular pathology : the American journal of surgical pathology, part B 32 21326037
2011 The transcription factor PlagL2 activates Mpl transcription and signaling in hematopoietic progenitor and leukemia cells. Leukemia 31 21263445
1998 Thrombopoietin stimulates VEGF release from c-Mpl-expressing cell lines and haematopoietic progenitors. FEBS letters 31 9506832
2016 Detection of CALR and MPL Mutations in Low Allelic Burden JAK2 V617F Essential Thrombocythemia. The Journal of molecular diagnostics : JMD 30 27855276
2002 A novel MPL point mutation resulting in thrombopoietin-independent activation. Leukemia 30 12145691
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2009 Clinical significance of Gata-1, Gata-2, EKLF, and c-MPL expression in acute myeloid leukemia. American journal of hematology 29 19097174
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