Affinage

MPL

Thrombopoietin receptor · UniProt P40238

Length
635 aa
Mass
71.2 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MPL (c-Mpl/TpoR/CD110) is a homodimeric type I cytokine receptor that transduces thrombopoietin (TPO) signals to control megakaryopoiesis, thrombopoiesis, and hematopoietic stem cell (HSC) production and self-renewal (PMID:8073287, PMID:9448308, PMID:17634189). Cryo-EM of the extracellular TPO–TpoR complex and cysteine-substitution mutagenesis establish that activation proceeds through ligand-induced homodimerization (PMID:11012211, PMID:37633268); the membrane-distal cytokine-receptor module forms the TPO-binding epitope, and proper receptor presentation depends on C-mannosylation of extracellular tryptophans and on JAK2, which chaperones MPL through the ER to the cell surface (PMID:24438083, PMID:24931576, PMID:26505790). Dimerization engages the membrane-proximal box 1 motif to activate the associated kinases JAK2 and TYK2, which phosphorylate STAT1/3/5 and drive downstream ERK/MAPK, PI3K/AKT, and PKC pathways (PMID:7534285, PMID:7543416, PMID:7605989, PMID:9446641, PMID:12145691). Signaling output is set by receptor geometry — engineered partial-agonist ligands decouple JAK/STAT from ERK/AKT/CREB, separating platelet production from HSC expansion (PMID:33384332, PMID:37633268). Signal magnitude is restrained by multiple negative regulators: c-Cbl ubiquitinates intracellular lysines K553/K573 to target the receptor for lysosomal and proteasomal degradation (PMID:19880496), the Lnk adaptor dampens STAT/AKT/MAPK output via its SH2 domain (PMID:15337790), and phospho-Y591 recruits SHP-1/SYK/BTK to limit ERK activation (PMID:24607955). Megakaryocyte/platelet MPL also clears circulating TPO, and loss of this scavenging causes thrombocytosis (PMID:10216080, PMID:24711413). MPL drives myeloproliferative neoplasia through gain-of-function transmembrane mutations (W515 variants, S505N) that force homodimerization and converge on residue W491 (PMID:31697803, PMID:31978223), and through mutant CALR, which binds the MPL extracellular domain as a rogue chaperone to stabilize and traffic a dimeric, constitutively active receptor (PMID:29288169, PMID:30902807, PMID:27716741); MPL expression itself is required for JAK2V617F-driven MPN (PMID:25339357). MPL is essential for development of severe congenital amegakaryocytic thrombocytopenia (CAMT), where mutations impair receptor surface presentation or TPO binding (PMID:24438083, PMID:23908116).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 High

    Established the core physiological role of MPL by showing it is the lineage-restricted regulator of platelet and megakaryocyte production and the clearance receptor for circulating TPO.

    Evidence c-mpl knockout mice with blood counts and megakaryocyte quantification

    PMID:8073287

    Open questions at the time
    • Did not define the signaling mechanism downstream of the receptor
    • Residual platelet production indicated MPL-independent thrombopoiesis pathways
  2. 1995 High

    Defined the immediate signaling cascade, showing TPO-MPL engagement activates JAK2 and TYK2 leading to STAT1/3/5 activation and DNA-binding complex formation.

    Evidence Immunoprecipitation, Western blotting, and gel-shift assays in factor-dependent hematopoietic cell lines

    PMID:7534285 PMID:7543416 PMID:7605989

    Open questions at the time
    • Initial kinase ordering ambiguous (JAK2 associated late after phosphorylation)
    • Membrane-proximal box 1 motif requirement defined by deletion only in heterologous cells
  3. 1996 High

    Defined the activation mechanism as ligand-induced homodimerization and established lineage-restricted transcriptional control of MPL.

    Evidence Cysteine-substitution forced-dimerization mutants in factor-dependent cells; GATA-1/Ets promoter transactivation assays

    PMID:11012211 PMID:8639837 PMID:8781421

    Open questions at the time
    • Structural basis of the dimer interface not resolved
    • Ectopic overexpression effects on non-megakaryocytic lineages not yet mechanistically explained
  4. 1998 High

    Extended MPL function beyond megakaryocytes to demonstrate a cell-intrinsic requirement for HSC production and self-renewal.

    Evidence Competitive and serial bone marrow transplantation and CFU-S assays in mpl-/- mice

    PMID:9448308

    Open questions at the time
    • Molecular effectors of HSC self-renewal downstream of MPL not identified
    • Did not separate HSC maintenance from megakaryocyte effects mechanistically
  5. 1998 Medium

    Diversified the downstream signaling repertoire, separating PKC-dependent mitogenesis from differentiation and linking MPL to VEGF release and Tec/Vav signaling.

    Evidence PKC inhibitor/downregulation, VEGF ELISA in receptor-matched cell lines, kinase and co-IP assays

    PMID:9091296 PMID:9446641 PMID:9506832

    Open questions at the time
    • Single-lab pharmacological dissection
    • Physiological relevance of VEGF/Tec branches in vivo untested
  6. 2002 Medium

    Connected MPL signaling to survival and stress responses, showing TPO inhibits p53-dependent apoptosis and modulates NF-kB, and that an intracellular activating mutation engages Ras/MAPK, JAK-STAT, and PI3K-Akt.

    Evidence p53-/- and Bax-/- epistasis in myelosuppression; IKK/NF-kB assays; W508S gain-of-function in Ba/F3

    PMID:11567994 PMID:11967992 PMID:12145691

    Open questions at the time
    • Single-lab studies
    • Relative contribution of each branch to in vivo survival not quantified
  7. 2004 High

    Identified the Lnk adaptor as an SH2-domain negative regulator that constrains TPO-MPL signaling strength and megakaryocyte output.

    Evidence Lnk overexpression/SH2 mutants and Lnk-/- mice with STAT/Akt/MAPK phosphorylation readouts

    PMID:15337790

    Open questions at the time
    • Precise docking site of Lnk on MPL not mapped
    • Interplay with other negative regulators not resolved
  8. 2007 High

    Established MPL's role in HSC quiescence in the osteoblastic niche and in HSC generation/expansion during definitive hematopoiesis.

    Evidence Anti-MPL neutralizing antibody and TPO gain-of-function with quiescence assays; in situ and reconstitution in Mpl-/- embryos

    PMID:17634189 PMID:18371409

    Open questions at the time
    • Transcriptional program linking MPL to beta1-integrin/CDK inhibitors not fully mapped
    • Niche-derived vs HSC-autonomous TPO contributions in development unresolved
  9. 2008 High

    Placed a c-Myb/p300 transcriptional repressor complex downstream of MPL signaling in megakaryocyte progenitor control.

    Evidence ENU suppressor screen and Mpl-/- x p300Plt6 genetic epistasis with transplantation

    PMID:18684867

    Open questions at the time
    • Direct molecular link between MPL signaling and c-Myb/p300 activity not established
    • Target genes of the repressor complex not defined
  10. 2009 High

    Defined the principal degradative negative-feedback mechanism: c-Cbl-mediated ubiquitination of intracellular lysines K553/K573 driving receptor turnover.

    Evidence Site-directed mutagenesis, c-Cbl knockdown/dominant-negative, ubiquitination and proliferation assays

    PMID:19880496

    Open questions at the time
    • Relative lysosomal vs proteasomal flux not quantified in vivo
    • How c-Cbl recruitment is timed relative to JAK activation unclear
  11. 2011 Medium

    Identified PLAGL2 and later NFIX as transcriptional activators of MPL that amplify JAK-STAT/AKT/ERK signaling and anti-apoptotic output.

    Evidence Promoter reporter/ChIP and signaling/rescue assays in leukemic cells and HSPCs

    PMID:21263445 PMID:29430853

    Open questions at the time
    • Single-lab promoter studies
    • Physiological vs pathological context of these regulators not distinguished
  12. 2012 Medium

    Linked wild-type MPL overexpression to leukemic survival, showing AML1-ETO/RUNX1-ETO induces MPL to drive PI3K/AKT and Bcl-xL-dependent survival and self-renewal.

    Evidence Retroviral overexpression cooperation in mice, pathway-specific inhibitors, shRNA, and apoptosis/self-renewal assays

    PMID:22337712 PMID:22613795

    Open questions at the time
    • Single-lab models
    • Direct mechanism by which the fusion induces MPL transcription not fully defined
  13. 2013 Medium

    Showed MPL maintains multipotent CD34+ progenitors and MEP development and that CAMT-mutant context redirects MPL output via altered FLI1 expression.

    Evidence iPSC-derived CAMT disease model with retroviral MPL rescue and lineage assays

    PMID:23908116

    Open questions at the time
    • Single-lab iPSC model
    • Mechanism linking MPL signaling to FLI1 regulation not defined
  14. 2014 High

    Refined the receptor lifecycle and physiology: JAK2 chaperones MPL trafficking and stabilizes surface expression, Y591 recruits SHP-1/SYK/BTK to dampen ERK, CAMT mutations disrupt surface presentation or TPO binding, and megakaryocyte/platelet MPL functions chiefly as a TPO scavenger to set platelet number.

    Evidence Proximity ligation/knockdown trafficking studies, SH2/PTB array and siRNA, surface-expression/binding mutagenesis, and PF4-Cre conditional knockout

    PMID:24438083 PMID:24607955 PMID:24711413 PMID:24931576 PMID:25143485

    Open questions at the time
    • TPO-scavenging vs proliferative signaling balance in disease incompletely separated
    • Structural epitope mapping inferred from mutagenesis, not direct structure
  15. 2014 High

    Established that MPL expression, not TPO ligand, is fundamental for JAK2V617F-driven myeloproliferative neoplasm.

    Evidence JAK2V617F transgenic mice crossed to Mpl-/- and Tpo-/- with disease phenotype readouts

    PMID:25339357

    Open questions at the time
    • Mechanism by which MPL is required for mutant JAK2 signaling not fully resolved
    • Did not address human MPN with the same precision
  16. 2017 High

    Defined mutant CALR as a direct MPL ligand whose lectin function and positively charged C-terminus drive binding and require intracellular MPL tyrosines for downstream activation.

    Evidence Co-IP, MPL intracellular tyrosine mutagenesis, CALR charge mutants, and cytokine-independent growth assays

    PMID:27716741 PMID:29288169

    Open questions at the time
    • Binding alone insufficient for transformation — activation requirements only partly defined
    • Stoichiometry of the CALR-MPL complex not resolved
  17. 2019 High

    Established the rogue-chaperone mechanism: mutant CALR stabilizes a dimeric MPL, protects its N-glycans, and traffics it to the surface for oncogenic activation, with debate over whether activation begins intracellularly.

    Evidence Glycan processing, N-glycosylation/hydrophobic-patch mutagenesis, thermal stability, trafficking inhibition, and trypsin surface-removal assays

    PMID:30902807 PMID:31462733

    Open questions at the time
    • Timing of activation (intracellular vs surface) not fully reconciled between studies
    • Single-lab subcellular localization analyses
  18. 2020 High

    Comprehensively mapped activating transmembrane-domain mutations and showed they activate by forcing TM homodimerization, all converging on residue W491.

    Evidence Deep mutational scanning and protein-complementation dimerization assays in Ba/F3 cells with structure-guided W491 mutagenesis

    PMID:31697803 PMID:31978223

    Open questions at the time
    • Structural mechanism of W491 dependence not directly visualized
    • Second-site modifier mechanisms not individually characterized
  19. 2021 High

    Demonstrated that receptor dimerization geometry tunes biased signaling, enabling partial agonists that preserve HSC properties while blocking oncogenic colony formation.

    Evidence Engineered diabody ligands with phospho-pathway analysis, scRNA-seq, and HSC/ET colony assays

    PMID:33384332

    Open questions at the time
    • In vivo therapeutic efficacy of biased ligands not established here
    • Structural basis of geometry-dependent bias defined later
  20. 2023 High

    Provided the high-resolution structural basis for homodimeric MPL activation and used it to engineer biased TPO variants that uncouple platelet production from HSC expansion.

    Evidence 3.4 Å cryo-EM of the TPO-TpoR extracellular complex with structure-guided TPOmod variants and in vivo/in vitro functional validation

    PMID:37633268

    Open questions at the time
    • Intracellular/transmembrane activation steps not captured in the extracellular structure
    • Full-length receptor-JAK2 assembly not visualized
  21. 2024 Medium

    Identified PF4 as an alternative MPL ligand that activates JAK2-STAT3/5 to drive platelet aggregation, extending MPL signaling to thrombo-inflammatory contexts.

    Evidence Binding, phosphorylation Western blots, platelet aggregation, and pharmacological MPL-JAK2 inhibition

    PMID:37883794

    Open questions at the time
    • Single-lab finding
    • Binding site of PF4 on MPL relative to TPO not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how dimerization geometry is structurally translated into biased intracellular kinase output and how the membrane-spanning JAK2-MPL signaling module is assembled and regulated.
  • No structure of the full-length receptor with JAK2
  • Conflicting models of intracellular vs surface activation by mutant CALR
  • Mechanistic coupling between receptor geometry and pathway selectivity unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4
Partners
CALRCBLJAK2LNKPF4STAT5THPOTYK2
Complex memberships
MPL-JAK2 complexTPO-MPL receptor complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 c-mpl-deficient mice show 85% reduction in platelets and megakaryocytes but normal other hematopoietic lineages, establishing that c-Mpl specifically regulates megakaryocytopoiesis and thrombopoiesis through activation by TPO; increased circulating TPO in knockout mice indicates c-Mpl-mediated clearance of TPO. Gene targeting (knockout mice), complete blood counts, megakaryocyte quantification Science High 8073287
1995 TPO binding to c-Mpl induces tyrosine phosphorylation of JAK2, Shc, and c-Mpl itself within 1 min; JAK2 physically associates with c-Mpl late (20–60 min after stimulation), after its initial tyrosine phosphorylation, suggesting JAK2 may not be the initiating kinase. Phospholipase C-gamma showed little phosphorylation and PI3K showed no tyrosine phosphorylation in response to TPO. Immunoprecipitation, Western blotting with phosphotyrosine antibodies, co-immunoprecipitation in BaF3/mMpl cells The Journal of biological chemistry High 7534285
1995 Activation of the TPO receptor c-MPL 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. Immunoprecipitation, Western blotting, gel-shift assays in factor-dependent hematopoietic cell lines Experimental hematology High 7543416
1995 The membrane-proximal box 1 sequence motif of c-Mpl cytoplasmic domain is critical for gene regulation and STAT protein activation involving JAK2; c-mpl and IL-3R activate comparable gene regulatory responses but do not functionally interact through shared receptor subunits. Deletion mutants expressed in transiently transfected hepatoma cells and fibroblasts, STAT DNA-binding activity assays Blood Medium 7605989
1996 The MPL promoter requires GATA-1 (binding at -70) and Ets proteins (binding at -15 and downstream of GATA motif) for megakaryocyte-specific expression; GATA-1 and Ets proteins Ets-1 and Fli-1 additively trans-activate the MPL promoter. Promoter deletion analysis, in vitro binding assays, transactivation assays in heterologous cells Blood High 8639837
1996 Ectopic retroviral expression of c-mpl in mice causes erythroblastic proliferation, hepatosplenomegaly, and thrombocytopenia, demonstrating that overexpression of c-Mpl on non-megakaryocytic progenitors promotes erythroid and granulocyte-macrophage colony expansion. Retroviral infection of adult mice, histology, in vitro clonogenic progenitor assays Blood Medium 8781421
1996 Constitutively active c-Mpl receptor mutants generated by substitution of cysteine residues into a dimer-interface homology domain force ligand-independent homodimerization, constitutive receptor phosphorylation, and autonomous cell growth/tumorigenicity, establishing that ligand-induced homodimerization is the normal activation mechanism. Site-directed mutagenesis, expression in factor-dependent cells, phosphorylation analysis, tumorigenicity assay Stem cells High 11012211
1997 Tec protein-tyrosine kinase is rapidly tyrosine-phosphorylated and activated upon TPO stimulation of c-Mpl; Vav protein is tyrosine-phosphorylated by TPO and constitutively associated with Tec, placing Tec downstream of c-Mpl signaling. Immunoprecipitation, kinase activity assay, co-immunoprecipitation in TPO-dependent cell line Experimental hematology Medium 9091296
1998 mpl-/- mice have 4- to 12-fold fewer hematopoietic preprogenitor cells and 8- to 10-fold fewer CFU-S than wild-type; this defect is intrinsic to hematopoietic cells (not microenvironment) and mpl-/- bone marrow fails to compete in long-term reconstitution, establishing that TPO/c-Mpl signaling is essential for hematopoietic stem cell production and self-renewal. Competitive bone marrow transplantation, CFU-S assays, serial transplantation in mpl-/- mice Proceedings of the National Academy of Sciences High 9448308
1998 TPO activates PKC isoforms alpha and beta in c-Mpl-expressing UT-7 cells, and PKC activation is required for TPO-induced mitogenesis but not for TPO-induced megakaryocytic differentiation (GpIIb expression). PKC translocation assay, PKC inhibitor (GF109203X), phorbol ester downregulation, proliferation and differentiation assays Blood Medium 9446641
1998 TPO stimulates VEGF release from c-Mpl-expressing cell lines (CMK, UT-7/mpl) and CD34+ hematopoietic progenitors but not from parental UT-7 cells lacking c-Mpl, linking c-Mpl signaling to VEGF production during megakaryocytic differentiation. VEGF ELISA in conditioned medium, UT-7 vs UT-7/mpl comparison, RT-PCR for VEGF mRNA in CD34+ cultures FEBS letters Medium 9506832
1999 High-level Mpl expression on megakaryocytes and platelets is not regulated by TPO at the transcriptional or translational level; however, excess circulating TPO leads to Mpl disappearance from platelets via catabolism, establishing receptor-mediated clearance as the TPO regulatory mechanism. RNase protection analysis, Western blotting in TPO-knockout and TPO-stimulated mice, in vitro megakaryocyte cultures with/without TPO Blood Medium 10216080
2001 Mpl ligand (TPO) prevents lethal myelosuppression by inhibiting p53-dependent apoptosis; p53-/- mice survive lethal myelosuppression without Mpl-L, whereas Bax-/- mice still require Mpl-L, placing Mpl-L action downstream of p53 but independently of Bax. In vivo myelosuppression with p53-/- and Bax-/- mice, survival assay, p53/p21 expression analysis Blood Medium 11567994
2002 A spontaneous mutation of MPL (W508S) in the intracellular domain constitutively activates SHC-Ras-Raf-MAPK/JNK, JAK-STAT, and PI3K-Akt-Bad signaling pathways and induces factor-independent growth of Ba/F3 cells. Ba/F3 cell growth assay, intracellular signaling pathway analysis by Western blotting Leukemia Medium 12145691
2002 Mpl receptor signaling activates IKK transiently and then reduces IKK activity, leading to decreased NF-κB DNA binding activity in megakaryocytes; proliferating megakaryocytes display constitutive NF-κB (p50 homodimer and p50-p65 heterodimer) activity. IKK kinase assay, NF-κB gel-shift and reporter assay in megakaryocytic cell line Journal of cellular biochemistry Medium 11967992
2004 The adaptor protein Lnk negatively regulates TPO-induced mpl signaling via its SH2 domain; Lnk overexpression attenuates STAT3, STAT5, Akt, and MAPK activation by TPO, and Lnk-deficient mice show enhanced megakaryocyte numbers and ploidy and hypersensitivity to TPO. Overexpression and SH2-domain mutants in cell lines and primary cells, Lnk-/- mice, STAT/Akt/MAPK phosphorylation assays The Journal of experimental medicine High 15337790
2007 THPO/MPL signaling in long-term HSCs upregulates beta1-integrin and cyclin-dependent kinase inhibitors, maintaining HSC quiescence in the osteoblastic niche; anti-MPL neutralizing antibody (AMM2) reduces quiescent LT-HSC numbers and allows exogenous HSC engraftment without irradiation. Anti-MPL neutralizing antibody treatment, exogenous TPO administration, quiescence assays (BrdU, CFSE), gene expression analysis in murine bone marrow Cell stem cell High 18371409
2007 Mpl receptor is expressed in AGM HSC clusters and fetal liver as early as E10.5; Mpl-/- embryos show delayed AGM HSC production with a self-renewal defect and decreased fetal liver HSC amplification, establishing a dual role for Mpl in generation and expansion of HSCs during definitive hematopoiesis. In situ hybridization, hematopoietic progenitor assays, long-term reconstitution in Mpl-/- embryos at multiple developmental stages Development High 17634189
2008 A point mutation (Y630N) in p300 that disrupts the p300–c-Myb interaction suppresses thrombocytopenia in Mpl-/- mice by expanding megakaryocyte progenitors, placing the c-Myb/p300 transcriptional repressor complex downstream of MPL signaling in control of megakaryopoiesis. ENU mutagenesis screen, genetic epistasis (Mpl-/- x p300Plt6), bone marrow transplantation, megakaryocyte progenitor quantification Blood High 18684867
2009 After TPO stimulation, c-Mpl is ubiquitinated on intracellular lysines K553 and K573 by the E3 ubiquitin ligase c-Cbl, leading to degradation via both lysosomal and proteasomal pathways; mutation of these lysines to arginine reduces ubiquitination and degradation and causes hyperproliferation. Site-directed mutagenesis, siRNA knockdown of c-Cbl, dominant-negative c-Cbl overexpression, ubiquitination assay, cell proliferation assay Blood High 19880496
2014 Mpl expression on megakaryocytes and platelets is dispensable for thrombopoiesis but essential to prevent myeloproliferation; mice lacking Mpl only on megakaryocytes/platelets (PF4-Cre-driven deletion) develop thrombocytosis and megakaryocytosis due to failure to absorb excess TPO, establishing that TPO scavenging by megakaryocyte/platelet Mpl is the key regulator of platelet number. Conditional knockout (Mpl^PF4cre/PF4cre mice), megakaryocyte/platelet counting, progenitor assays, TPO level measurement Proceedings of the National Academy of Sciences High 24711413
2014 MPL is required for development of JAK2V617F-induced myeloproliferative neoplasm; JAK2V617F(+)Mpl(-/-) mice show reduced thrombocythemia, neutrophilia, splenomegaly, and neoplastic stem cell pool compared with JAK2V617F(+) mice, whereas TPO loss only mildly affects the disease, establishing that MPL expression (not TPO) is fundamental for MPN development. Genetic epistasis using JAK2V617F transgenic mice crossed to Mpl-/- and Tpo-/- mice, complete blood counts, spleen weights, FACS of stem cell populations Blood High 25339357
2014 JAK2 levels regulate c-Mpl stability and cell-surface expression; decrease in JAK2 or MPL protein expression, or JAK2 inhibition, suppresses TPO-induced antiproliferative/differentiation signaling, and JAK2 inhibitors at low doses paradoxically increase megakaryocyte production in vitro and in vivo. siRNA knockdown, JAK2 chemical inhibitors, cell proliferation and differentiation assays in UT7-MPL cells and primary megakaryocytes, in vivo mouse experiments Blood Medium 25143485
2014 CAMT-associated mutations in c-Mpl principally cause defective receptor presentation on the cell surface; the F104S CAMT mutant reaches the cell surface but is defective in TPO binding; residues in Domain 1 E-F and A-B loops and Domain 2 F'-G' loop of the membrane-distal CRM comprise the TPO-binding epitope. Cell-surface expression assays, TPO binding assays, site-directed mutagenesis of domain 1 and 2 residues Growth factors Medium 24438083
2014 Mpl and JAK2 associate on both intracellular and plasma membranes (shown by proximity ligation assay); JAK2 knockdown traps Mpl in the endoplasmic reticulum, supporting a chaperone role for JAK2 in Mpl trafficking. Mpl reaches the plasma membrane via both conventional ER-Golgi and autolysosome secretory pathways. Proximity ligation assay, siRNA knockdown of JAK2, subcellular fractionation, electron microscopy with miniSOG-Mpl fusion, surface biotinylation Traffic Medium 24931576
2014 Phosphorylation of c-Mpl tyrosine Y591 is induced by TPO; Y591F mutation decreases total receptor phosphorylation and increases pERK1/2; Y591 recruits SHP-1, SYK, and BTK via SH2/PTB domains, and SYK mediates the increased ERK1/2 phosphorylation seen when Y591 is absent, identifying a negative regulatory pathway. Site-directed mutagenesis, SH2/PTB domain microarray, siRNA knockdown of SYK/BTK/SHP-1, 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 abolish downstream signaling. Mass spectrometry identification of C-mannosylation sites, site-directed mutagenesis, JAK-STAT signaling assays Biochemical and biophysical research communications Medium 26505790
2015 CD110+ (MPL+) colorectal cancer tumor-initiating cells are driven to liver metastasis by TPO through activation of lysine degradation; lysine catabolism generates acetyl-CoA used in p300-dependent LRP6 acetylation (triggering tyrosine phosphorylation of LRP6 and Wnt signaling) and glutamate (modulating redox status); TPO-mediated c-myc induction recruits chromatin modifiers to regulate metabolic gene expression. Metabolic labeling, acetylation assays, co-immunoprecipitation, siRNA knockdown, xenograft liver metastasis assays Cell stem cell Medium 26140605
2017 Mutant CALR binds to the extracellular domain of MPL; binding requires the lectin-dependent function of mutant CALR but not its chaperone or polypeptide-binding functions; the positive charge of the mutant CALR C terminus determines both MPL binding and signaling activation; three tyrosine residues within the intracellular domain of MPL are required to activate downstream signaling; binding alone is insufficient for cytokine-independent growth. Co-immunoprecipitation, domain mutagenesis of MPL intracellular tyrosines, charge-altering mutants of CALR C terminus, cytokine-independent growth assays Blood High 29288169
2019 Mutant CALR acts as a rogue chaperone for TpoR/MPL: its new positively charged C-terminal sequence stabilizes a dimeric TpoR state and transports it (including traffic-defective TpoR mutants like R102P) to the cell surface bypassing quality control; mutant CALR protects N117-linked glycans from Golgi processing; a hydrophobic patch in the TpoR extracellular domain is required for mutant CALR to induce TpoR thermal stability and initial intracellular activation; full activation requires cell-surface localization of TpoR. Co-immunoprecipitation, glycan processing analysis, mutagenesis of N-glycosylation sites and hydrophobic patch, surface expression assays, thermal stability assays, transformation assays Blood High 30902807
2019 Mutant CALR accumulates in the Golgi apparatus and its entrance into the secretory pathway and N-glycan interaction are required for oncogenic MPL activation; mutant CALR-dependent MPL activation is resistant to blockade of intracellular protein trafficking, suggesting MPL is activated before reaching the cell surface; however, removal of MPL from the cell surface with trypsin shuts down downstream activation, and mutant CALR and MPL interact on the cell surface. Subcellular localization studies, trypsin cell-surface removal, inhibitors of intracellular trafficking, co-immunoprecipitation Leukemia Medium 31462733
2020 Deep mutational scanning of all single amino acid substitutions in the MPL transmembrane domain identified W515L/K/R/A and S505N as constitutively activating driver mutations, plus 7 novel activating mutations and many second-site modifiers; all canonical activating TMD mutations depend on residue W491 for activation, as does eltrombopag, identifying W491 as a convergence point for TpoR activation. Deep mutational scanning in Ba/F3 cells, cytokine-independent growth assay, structure-guided mutagenesis of W491 Blood High 31697803
2020 MPL mutations L498W and H499C/Y activate TpoR by strongly driving homodimerization via the transmembrane domain (shown by protein complementation assay); W491 is required for activation by L498W, H499C, S505N, W515K, and eltrombopag, establishing a common dimerization/activation path through the TM domain. Protein complementation dimerization assay, partial saturation mutagenesis, signaling assays Blood High 31978223
2021 Surrogate bispecific antibody (diabody) ligands that homodimerize TpoR in different geometries produce graded signaling outputs from full to partial TPO agonism, decoupling JAK/STAT from ERK/AKT/CREB activation; partial agonistic diabodies preserve HSC stem-like properties and block oncogenic colony formation in essential thrombocythemia through inverse agonism. Diabody engineering, signaling pathway analysis (phospho-STAT/ERK/AKT/CREB), single-cell RNA sequencing, HSC self-renewal assays, ET colony formation assays Proceedings of the National Academy of Sciences High 33384332
2023 Cryo-EM structure of the extracellular TPO-TpoR (MPL) signaling complex at 3.4 Å reveals the basis for homodimeric MPL activation and structural explanation for loss-of-function thrombocytopenia mutations; structure-guided engineering of TPO variants (TPOmod) as partial agonists decoupled JAK/STAT from ERK/AKT/CREB activation, driving megakaryopoiesis/platelet production without significant HSC expansion, demonstrating functional uncoupling of TPO's dual roles. Cryo-EM structure determination (3.4 Å), structure-guided protein engineering, signaling pathway analysis, in vivo mouse platelet/HSC assays, in vitro human HSC culture Cell High 37633268
2024 PF4 (platelet factor 4) binds and activates c-Mpl on platelets, leading to JAK2 activation and STAT3/STAT5 phosphorylation, resulting in platelet aggregation; c-Mpl-JAK2 pathway inhibition blocks platelet aggregation to PF4, VITT sera, and PF4/VITT IgG combinations. Binding assays, phosphorylation (JAK2, STAT3, STAT5) Western blotting, platelet aggregation assay, pharmacological inhibition of c-Mpl-JAK2 Blood Medium 37883794
2011 Transcription factor PLAGL2 upregulates Mpl transcription via two consensus sites in its proximal promoter; PLAGL2-expressing leukemic cells show hyper-activation of JAK2 and downstream STAT5, Akt, and Erk1/2 in response to THPO ligand. Promoter reporter assay, ChIP/binding site analysis, signaling phosphorylation assays in PLAGL2-expressing cells Leukemia Medium 21263445
2012 Wild-type MPL expression is increased in RUNX1-ETO AML and activates PI3K/AKT (but not ERK/MEK) pathway as a critical antiapoptotic mediator; Mpl overexpression cooperates with RUNX1-ETO to induce AML in mice, and leukemic cells are sensitive to THPO-dependent survival signals through PI3K/AKT. Retroviral Mpl overexpression in mice, PI3K/AKT and MEK/ERK inhibitors, apoptosis assays, primary AML sample analysis Blood Medium 22613795
2012 AML1-ETO induces MPL expression, which activates THPO/MPL signaling to upregulate Bcl-xL, controlling survival, cell-cycle reentry, and self-renewal in AML1-ETO-expressing cells; MPL-regulated Bcl-xL is essential for AML1-ETO preleukemic cell survival. shRNA knockdown of MPL, Bcl-xL, and THPO; cell cycle and apoptosis assays; self-renewal colony assays; primary AML sample correlation analysis Blood Medium 22337712
2013 MPL-mediated signaling is essential for maintenance of the CD34+ multipotent hematopoietic progenitor population and development of CD41+GPA+ MEP population; MPL overexpression promotes erythropoiesis in normal HPCs but impairs erythropoiesis and increases aberrant megakaryocyte production in CAMT HPCs, correlating with differential FLI1 transcription factor expression. iPSC-derived CAMT disease model, retroviral MPL transduction, lineage differentiation assays, FLI1 expression analysis The Journal of clinical investigation Medium 23908116
2015 c-Mpl is expressed on osteoblasts and osteoclasts; c-Mpl-/- mice have higher bone mass with increased osteoblasts and osteoclasts; c-Mpl-/- osteoblasts show increased cell cycle activity and enhanced osteoclastogenesis in co-culture without affecting MCSF/OPG/RANKL or EphrinB2-EphB2/B4 pathways. Bone histomorphometry, cell cycle analysis, in vitro co-culture osteoblast-osteoclast assays, RT-PCR and functional assays for signaling pathways in c-Mpl-/- mice Journal of cellular biochemistry Medium 26375403
2016 Morpholino knockdown of mpl (but not epor or csf3r) significantly attenuates the thrombocytosis and HSC/progenitor expansion caused by mutant CALR expression in zebrafish, establishing that mutant CALR acts through an mpl-dependent mechanism to activate jak-stat signaling. Morpholino knockdown in zebrafish, CALR mutant expression, thrombocyte counting, jak-stat signaling analysis, JAK inhibitor treatment Blood cancer journal Medium 27716741
2018 NFIX transcription factor binds the proximal c-Mpl promoter and transcriptionally activates it; Nfix overexpression in HSPCs elevates c-Mpl transcripts and cell surface protein and increases STAT5 phosphorylation; blocking c-MPL signaling (by TPO removal or neutralizing antibody) negates the anti-apoptotic effect of Nfix overexpression. ChIP/promoter binding assay, retroviral overexpression, c-Mpl protein and mRNA quantification, STAT5 phosphorylation assay, neutralizing antibody blockade Stem cells Medium 29430853

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 602 18371409
1994 Thrombocytopenia in c-mpl-deficient mice. Science (New York, N.Y.) 576 8073287
2014 CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 437 24402162
2010 Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 419 20428194
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 323 9448308
1995 The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood 275 7529061
2015 Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood 222 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
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 164 7543416
1997 Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia. Blood 161 9354672
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 147 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
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 107 24711413
2004 Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis. Proceedings of the National Academy of Sciences of the United States of America 98 15269348
1994 Structure and transcription of the human c-mpl gene (MPL). Genomics 98 8020956
1996 Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis. Blood 94 8839850
2019 Calreticulin mutants as oncogenic rogue chaperones for TpoR and traffic-defective pathogenic TpoR mutants. Blood 91 30902807
1998 Hematopoietic deficiencies in c-mpl and TPO knockout mice. Stem cells (Dayton, Ohio) 91 9474742
2008 JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia 85 18754026
2017 Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. Blood 80 29288169
2009 Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood 77 19880496
2020 MPL Adjuvant Contains Competitive Antagonists of Human TLR4. Frontiers in immunology 75 33178204
2014 The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm. Blood 70 25339357
2008 JAK and MPL mutations in myeloid malignancies. Leukemia & lymphoma 65 18297515
2006 Isolation and characterization of human myeloid progenitor populations--TpoR as discriminator between common myeloid and megakaryocyte/erythroid progenitors. Experimental hematology 56 16647566
2019 Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface. Leukemia 50 31462733
2014 JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation. Blood 50 25143485
1996 Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells. Leukemia 50 8751457
1996 Expression of the receptor MPL and proliferative effects of its ligand thrombopoietin on human leukemia cells. Leukemia 49 8637239
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
2014 Mpl traffics to the cell surface through conventional and unconventional routes. Traffic (Copenhagen, Denmark) 46 24931576
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
2012 The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO. Blood 44 22337712
2020 Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning. Blood 42 31697803
2016 MPL expression on AML blasts predicts peripheral blood neutropenia and thrombocytopenia. Blood 42 27574191
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
1995 Signal transduction by the receptors for thrombopoietin (c-mpL) and interleukin-3 in hematopoietic and nonhematopoietic cells. Blood 41 7605989
2017 Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis. Frontiers in endocrinology 40 28955303
2011 The thrombopoietin/MPL pathway in hematopoiesis and leukemogenesis. Journal of cellular biochemistry 39 21360575
1998 Protein kinase C mediates the mitogenic action of thrombopoietin in c-Mpl-expressing UT-7 cells. Blood 39 9446641
1996 Ectopic expression of murine TPO receptor (c-mpl) in mice is pathogenic and induces erythroblastic proliferation. Blood 39 8781421
2018 MPL and CpG combination adjuvants promote homologous and heterosubtypic cross protection of inactivated split influenza virus vaccine. Antiviral research 38 29885376
2009 CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells. Biochemical and biophysical research communications 38 19341705
2001 Mpl ligand prevents lethal myelosuppression by inhibiting p53-dependent apoptosis. Blood 37 11567994
2024 PF4 activates the c-Mpl-Jak2 pathway in platelets. Blood 36 37883794
2023 Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis. Cell 34 37633268
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
2013 Different mutations of the human c-mpl gene indicate distinct haematopoietic diseases. Journal of hematology & oncology 29 23351976
2009 Clinical significance of Gata-1, Gata-2, EKLF, and c-MPL expression in acute myeloid leukemia. American journal of hematology 29 19097174
2008 Point mutation in the gene encoding p300 suppresses thrombocytopenia in Mpl-/- mice. Blood 29 18684867
1994 The mpl ligand: molecular and cellular biology of the critical regulator of megakaryocyte development. Stem cells (Dayton, Ohio) 29 7696972
2021 Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors. Proceedings of the National Academy of Sciences of the United States of America 26 33384332
1997 Tec protein-tyrosine kinase is involved in the thrombopoietin/c-Mpl signaling pathway. Experimental hematology 26 9091296
1996 Expression of thrombopoietin and thrombopoietin receptor MPL in human leukemia-lymphoma and solid tumor cell lines. Leukemia research 25 8960108
2017 Identification of MPL R102P Mutation in Hereditary Thrombocytosis. Frontiers in endocrinology 24 28979237
2002 Signaling by the Mpl receptor involves IKK and NF-kappaB. Journal of cellular biochemistry 24 11967992
2019 The role of the thrombopoietin receptor MPL in myeloproliferative neoplasms: recent findings and potential therapeutic applications. Expert review of hematology 23 31092065
1999 Thrombopoietin and the c-Mpl receptor: insights from gene targeting. The international journal of biochemistry & cell biology 23 10582337
1996 Studies of the c-Mpl thrombopoietin receptor through gene disruption and activation. Stem cells (Dayton, Ohio) 22 11012212
2018 Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit. Disease models & mechanisms 21 29666143
2016 Expression of CALR mutants causes mpl-dependent thrombocytosis in zebrafish. Blood cancer journal 21 27716741
2015 C-Mpl Is Expressed on Osteoblasts and Osteoclasts and Is Important in Regulating Skeletal Homeostasis. Journal of cellular biochemistry 21 26375403
1995 c-mpl expression in hematologic disorders. Leukemia & lymphoma 21 7773160
2014 Functional characterization of c-Mpl ectodomain mutations that underlie congenital amegakaryocytic thrombocytopenia. Growth factors (Chur, Switzerland) 20 24438083
2009 Gene therapy of MPL deficiency: challenging balance between leukemia and pancytopenia. Molecular therapy : the journal of the American Society of Gene Therapy 20 19844195
2004 Thrombopoietin receptor (Mpl) expression by megakaryocytes in myeloproliferative disorders. The Journal of pathology 20 15095485
1999 High-level expression of Mpl in platelets and megakaryocytes is independent of thrombopoietin. Blood 19 10216080
1995 The physiologic role and therapeutic potential of the Mpl-ligand in thrombopoiesis. Stem cells (Dayton, Ohio) 19 8590859
2018 Nfix Promotes Survival of Immature Hematopoietic Cells via Regulation of c-Mpl. Stem cells (Dayton, Ohio) 18 29430853
2023 The influence of MPL addition on structure, interfacial compositions and physicochemical properties on infant formula fat globules. Food research international (Ottawa, Ont.) 17 37120219
2021 The MPL mutation. International review of cell and molecular biology 17 34756243
2019 Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F- and MPLW515 L-positive myelofibrosis. Genes, chromosomes & cancer 17 31135094
2018 Anti-c-Mpl antibodies in immune thrombocytopenia suppress thrombopoiesis and decrease response to rhTPO. Thrombosis research 17 30199786
2000 Megakaryocyte growth and development factor (MGDF): an Mpl ligand and cytokine that regulates thrombopoiesis. Cytokines, cellular & molecular therapy 17 10976539
2021 Platelet enhancement by Carica papaya L. leaf fractions in cyclophosphamide induced thrombocytopenic rats is due to elevated expression of CD110 receptor on megakaryocytes. Journal of ethnopharmacology 16 33831466
2015 Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages. Molecular immunology 16 25829245
2009 Failure to achieve a threshold dose of CD34+CD110+ progenitor cells in the graft predicts delayed platelet engraftment after autologous stem cell transplantation for multiple myeloma. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 16 19822297
2015 JAK2 V617F, MPL, and CALR Mutations in Korean Patients with Essential Thrombocythemia and Primary Myelofibrosis. Journal of Korean medical science 15 26130950
2014 Phosphorylated c-Mpl tyrosine 591 regulates thrombopoietin-induced signaling. Experimental hematology 15 24607955
2014 A hyperactive Mpl-based cell growth switch drives macrophage-associated erythropoiesis through an erythroid-megakaryocytic precursor. Blood 15 25343958
1996 Dissection of c-Mpl and thrombopoietin function: studies of knockout mice and receptor signal transduction. Stem cells (Dayton, Ohio) 15 11012211
2020 MPL mutations in essential thrombocythemia uncover a common path of activation with eltrombopag dependent on W491. Blood 14 31978223
2017 Fungal lectin MpL enables entry of protein drugs into cancer cells and their subcellular targeting. Oncotarget 14 28460472
2017 c-MPL provides tumor-targeted T-cell receptor-transgenic T cells with costimulation and cytokine signals. Blood 14 29079582
2009 JAK2 and MPL gene mutations in V617F-negative myeloproliferative neoplasms. Leukemia research 14 19643476
2008 Impact of chicken thrombopoietin and its receptor c-Mpl on hematopoietic cell development. Experimental hematology 14 18243490
2020 c-Mpl and TPO expression in the human central nervous system neurons inhibits neuronal apoptosis. Aging 13 32341206
2019 Indirubin regulates MPL and TNF expression in peripheral blood mononuclear cells from patients with primary immune thrombocytopenia. Experimental hematology 13 31014934

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