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Showing MPIG6B — G6B is a alias.

MPIG6B

Megakaryocyte and platelet inhibitory receptor G6b · UniProt O95866

Length
241 aa
Mass
26.2 kDa
Annotated
2026-06-10
24 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MPIG6B (G6b-B) is a megakaryocyte- and platelet-expressed inhibitory immunoreceptor that restrains ITAM/hemi-ITAM-driven activation to control platelet production and reactivity (PMID:17186946, PMID:23112346). Its cytoplasmic tail carries two ITIM/ITSM tyrosines (Y212/Y238) that become phosphorylated upon platelet stimulation and serve as docking sites for the tyrosine phosphatases SHP-1 and SHP-2, with SHP-2 binding through its tandem SH2 domains at ~100-fold higher affinity and requiring only single-motif phosphorylation, whereas SHP-1 requires dual phosphorylation (PMID:11544253, PMID:17186946, PMID:23185356). Through these phosphatases, G6b-B suppresses constitutive and agonist-induced signaling by the GPVI-FcRγ and CLEC-2 receptors and dampens platelet aggregation in response to collagen-related peptide and ADP (PMID:17311996, PMID:18955485, PMID:29891536). The extracellular Ig-like domain engages heparan sulfate, binding heparin with high affinity in an electrostatic manner and recognizing the heparan sulfate chains of perlecan; multivalent heparin induces receptor dimerization and triggers Shp1/Shp2-dependent inhibitory signaling (PMID:15848171, PMID:31436532). Loss of G6b-B or uncoupling of its ITIMs from Shp1/Shp2 causes macrothrombocytopenia, megakaryocyte clustering and myelofibrosis driven by elevated metalloproteinase-mediated shedding of GPVI and GPIbα, defective proplatelet formation, and unrestrained Syk kinase activity, and additionally impairs an early GATA-1- and thrombopoietin-dependent step of megakaryocyte maturation (PMID:23112346, PMID:29891536, PMID:35134123, PMID:36269841).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 High

    Established that G6b-B is an ITIM-bearing receptor whose phosphorylation recruits the SHP phosphatases, defining its candidate inhibitory wiring.

    Evidence Site-directed mutagenesis and co-immunoprecipitation of epitope-tagged protein in K562 and COS-7 cells

    PMID:11544253

    Open questions at the time
    • Done in heterologous cell lines, not platelets
    • No physiological agonist or downstream functional output tested
  2. 2005 Medium

    Identified the extracellular ligand chemistry, showing the Ig-like domain binds sulfated glycans, pointing to heparin/heparan sulfate recognition.

    Evidence ELISA-based competitive heparin binding assay with recombinant extracellular domain

    PMID:15848171

    Open questions at the time
    • Physiological ligand not yet identified
    • In vitro binding only, no cellular consequence
  3. 2006 Medium

    Placed G6b-B on the platelet surface and confirmed stimulation-dependent phosphorylation and SHP-1 association in primary cells.

    Evidence Platelet surface proteomics plus immunoprecipitation and Western blot from stimulated platelets

    PMID:17186946

    Open questions at the time
    • Correlative association, no functional consequence shown
    • SHP-2 binding not assessed here
  4. 2007 Medium

    Demonstrated directly that engaging G6b-B inhibits platelet activation, establishing its function as an inhibitory receptor.

    Evidence Platelet aggregation and calcium flux assays with anti-G6B cross-linking against ADP and CRP

    PMID:17311996

    Open questions at the time
    • Mechanism of inhibition not dissected
    • Antibody cross-linking is non-physiological engagement
  5. 2008 High

    Mapped the inhibitory target to ITAM/hemi-ITAM signaling by GPVI-FcRγ and CLEC-2 and showed ITIM-dependence, while finding it phosphatase-independent in this model.

    Evidence NFAT reporter assay in cell lines with ITIM mutagenesis and Src/Syk inhibitors

    PMID:18955485

    Open questions at the time
    • Phosphatase-independence in cell line conflicts with platelet data
    • Cell line model may not reflect megakaryocyte context
  6. 2012 High

    Resolved the molecular basis of phosphatase recruitment, distinguishing high-affinity single-motif SHP-2 binding from dual-phosphorylation-dependent SHP-1 binding.

    Evidence Reciprocal co-IP from human platelets with quantitative SH2-domain affinity measurements

    PMID:23185356

    Open questions at the time
    • Relative in vivo contribution of SHP-1 versus SHP-2 not resolved here
    • Functional readout of differential binding not tested
  7. 2012 High

    Defined the in vivo role through knockout, linking G6b-B loss to macrothrombocytopenia via receptor shedding and defective platelet production.

    Evidence G6b-B knockout mice with flow cytometry, metalloproteinase-inhibitor rescue, turnover and proplatelet assays

    PMID:23112346

    Open questions at the time
    • Full knockout cannot separate signaling from structural roles
    • Ligand driving signaling in vivo unidentified at this stage
  8. 2018 High

    Showed that the ITIM/Shp coupling itself is required in vivo, as ITIM-to-phenylalanine knock-in phenocopies knockout including myelofibrosis.

    Evidence G6b-B diY/F knock-in mice compared with KO and MK-specific Shp2 KO, with aggregation assays

    PMID:29891536

    Open questions at the time
    • Does not separate Shp1 from Shp2 contributions fully
    • Trigger for in vivo ITIM phosphorylation not defined here
  9. 2019 High

    Identified the physiological ligand as perlecan heparan sulfate and showed heparin-induced dimerization couples ligand engagement to Shp1/Shp2 inhibitory signaling.

    Evidence Affinity chromatography, proteomics, biophysics, genetic screen and functional assays in human platelets and mice

    PMID:31436532

    Open questions at the time
    • Spatial source of perlecan HS engaging the receptor in vivo not mapped
    • Stoichiometry of physiological clustering unresolved
  10. 2022 High

    Extended the role beyond signaling restraint to megakaryocyte maturation, implicating GATA-1 and thrombopoietin signaling in an early differentiation step.

    Evidence Spontaneous loss-of-function knock-in mouse with RNA-seq, Western blot and confocal imaging of the demarcation membrane system

    PMID:35134123

    Open questions at the time
    • Mechanism linking G6b-B to GATA-1 levels not established
    • Whether maturation defect is cell-intrinsic to the receptor or secondary unresolved
  11. 2023 High

    Identified elevated Syk activity as a driver of the knockout phenotype and showed thrombopoietin-mimetic rescue, framing G6b-B as a cell-intrinsic feedback regulator of platelet reactivity.

    Evidence Syk R41A genetic rescue in G6b KO, Syk inhibitors and romiplostim, with flow cytometry and aggregation assays

    PMID:36269841

    Open questions at the time
    • Direct biochemical link between G6b-B and Syk regulation not detailed
    • Relationship between Syk control and maturation defect not integrated
  12. 2024 Medium

    Demonstrated that G6b-B inhibitory signaling can be engaged in trans to suppress GPVI- and FcγRIIA-driven thrombosis, establishing therapeutic targetability.

    Evidence Bispecific scFv hetero-clustering with aggregation and microfluidic thrombus assays under arterial shear (preprint)

    PMID:38798354

    Open questions at the time
    • Preprint, single lab, not peer-reviewed
    • In vivo efficacy and safety not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How heparan sulfate ligand engagement is spatially and temporally controlled in the marrow niche, and how G6b-B mechanistically couples to GATA-1 and Syk during maturation, remain open.
  • No mechanism linking receptor signaling to GATA-1 regulation
  • Physiological source and geometry of perlecan-HS ligand undefined
  • Direct mode of Syk activity control not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-109582 Hemostasis 3 R-HSA-162582 Signal Transduction 3
Partners
HSPG2PLCG2PTPN11PTPN6SYK

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 G6b-B (MPIG6B) contains two ITIMs in its cytoplasmic tail and undergoes tyrosine phosphorylation upon pervanadate treatment; phosphorylation of tyrosine 211 is critical for interaction with SHP-1 and SHP-2, as shown by mutagenesis. Site-directed mutagenesis, co-immunoprecipitation, epitope-tagged recombinant protein expression in K562 and COS-7 cells The Journal of biological chemistry High 11544253
2005 The extracellular Ig-like domain of G6b-B binds heparin with high affinity in a predominantly electrostatic, salt-dependent manner, with an IC50 of ~0.5 µg/ml; other sulfated glycans showed weaker or no competition. ELISA-based heparin binding assay with competitive displacement using soluble heparin and other sulfated glycans FEBS letters Medium 15848171
2006 G6b-B is expressed on the platelet surface, undergoes tyrosine phosphorylation upon platelet stimulation, and associates with SHP-1 in stimulated platelets. Proteomics (LC-MS/MS of enriched platelet surface proteins), specific antibody immunoprecipitation, Western blot Molecular & cellular proteomics : MCP Medium 17186946
2007 Cross-linking of G6b-B on platelet surfaces significantly inhibits platelet aggregation and activation by ADP and collagen-related peptide (CRP) in a calcium-independent manner, demonstrating its function as an inhibitory receptor. Platelet aggregation assay using polyclonal anti-G6B antisera for cross-linking; calcium flux measurements Blood Medium 17311996
2007 G6b-B expression in CD4+ T cells is upregulated by interleukin-4 via a STAT6-binding cis-acting element in the 5'-flanking region of the gene. Luciferase reporter gene assay, electrophoretic mobility shift assay (EMSA), real-time PCR Human immunology Medium 17678728
2008 G6b-B inhibits both constitutive and agonist-induced ITAM/hemi-ITAM signaling by GPVI-FcRγ and CLEC-2 in a cell line model; this inhibition requires the conserved ITIM tyrosines of G6b-B but is independent of SHP-1, SHP-2, and SHIP. NFAT transcriptional reporter assay in cell lines, ITIM tyrosine mutagenesis, pharmacological inhibitors of Src/Syk family kinases The Journal of biological chemistry High 18955485
2012 G6b-B associates with both SHP-1 and SHP-2 in human platelets; the tandem SH2 domains of SHP-2 bind G6b-B with ~100-fold higher affinity than SHP-1; SHP-2 can bind when only one ITIM/ITSM motif is phosphorylated (N-terminal SH2 domain with ITIM being most important), whereas SHP-1 requires dual phosphorylation; Syk and PLCγ2 also demonstrate specificity for phosphorylated G6b-B motifs. Co-immunoprecipitation from human platelets, direct in vitro binding assays (surface plasmon resonance / affinity measurements), SH2 domain specificity profiling PloS one High 23185356
2012 G6b-B-deficient mice exhibit macrothrombocytopenia due to increased platelet turnover, enhanced metalloproteinase-mediated shedding of GPVI and GPIbα from megakaryocyte surfaces, reduced integrin-mediated functions, and defective proplatelet formation, establishing G6b-B as a major inhibitory receptor regulating megakaryocyte activation and platelet production. G6b-B knockout mouse model, flow cytometry, metalloproteinase inhibitor rescue experiments, platelet turnover assays, proplatelet formation assays Science signaling High 23112346
2018 Mutation of the two ITIM/ITSM tyrosines (Y212 and Y238) of G6b-B to phenylalanine (uncoupling from Shp1/Shp2) in mice causes macrothrombocytopenia, megakaryocyte clusters, and myelofibrosis similar to full G6b-B knockout; G6b-B inhibits CLEC-2-mediated platelet activation through Shp2. Transgenic knock-in mouse model (G6b-B diY/F), flow cytometry, platelet aggregation assays, comparison with G6b KO and MK-specific Shp2 KO mice Blood High 29891536
2019 The heparan sulfate proteoglycan perlecan is a G6b-B extracellular binding partner; the interaction is specifically mediated by heparan sulfate (HS) chains (not the protein core); heparin forms a high-affinity complex with G6b-B and mediates dimerization; binding to HS/multivalent heparin induces downstream signaling via Shp1 and Shp2 to inhibit platelet and megakaryocyte function. Immunohistochemistry, affinity chromatography, proteomics, in vitro biochemical binding assays, cell-based genetic screen, biophysical analysis (dimerization), functional assays with human platelets and genetically modified mice eLife High 31436532
2022 Loss of G6b-B impairs an early step of megakaryocyte differentiation: G6b-B-deficient megakaryocytes are smaller, have a less-developed demarcation membrane system, show globally reduced megakaryocyte-specific transcripts, decreased GATA-1 protein levels, and impaired thrombopoietin signaling. Spontaneous knock-in mutant mouse model (intronic SNV abolishing G6b-B expression), RNA sequencing, Western blot, confocal microscopy of demarcation membrane system Blood advances High 35134123
2023 In G6b-B knockout mice, elevated Syk kinase activity contributes to macrothrombocytopenia and loss of GPVI/α2β1; Syk loss-of-function (R41A) rescued macrothrombocytopenia and GPVI/α2β1 expression; romiplostim (thrombopoietin mimetic) rescued thrombocytopenia, GPVI expression, and collagen reactivity, suggesting G6b-B regulates a cell-intrinsic feedback mechanism controlling platelet reactivity. Genetic rescue (Syk R41A knock-in in G6b KO background), pharmacological treatment (Syk inhibitor BI1002494, dasatinib, romiplostim), flow cytometry, platelet aggregation assays Blood advances High 36269841
2024 Bispecific single-chain variable fragments (CAPRIs) that hetero-cluster G6b-B with GPVI-FcRγ or FcγRIIA (CD32A) inhibit collagen- or immune complex-induced platelet aggregation and thrombus formation under arterial shear, demonstrating that G6b-B's ITIM-mediated inhibitory signaling can be artificially engaged in trans to suppress ITAM-containing receptor activation. Bispecific scFv (bi-scFv) engineering, platelet aggregation assays, microfluidic thrombus formation assays under arterial shear, photochemical endothelial injury model bioRxivpreprint Medium 38798354

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 A comprehensive proteomics and genomics analysis reveals novel transmembrane proteins in human platelets and mouse megakaryocytes including G6b-B, a novel immunoreceptor tyrosine-based inhibitory motif protein. Molecular & cellular proteomics : MCP 122 17186946
2012 Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet function. Science signaling 66 23112346
2007 The novel inhibitory receptor G6B is expressed on the surface of platelets and attenuates platelet function in vitro. Blood 53 17311996
2019 Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. eLife 52 31436532
2008 G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2. The Journal of biological chemistry 47 18955485
2001 G6b, a novel immunoglobulin superfamily member encoded in the human major histocompatibility complex, interacts with SHP-1 and SHP-2. The Journal of biological chemistry 46 11544253
2018 Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice. Blood 37 29898956
2018 Uncoupling ITIM receptor G6b-B from tyrosine phosphatases Shp1 and Shp2 disrupts murine platelet homeostasis. Blood 28 29891536
2017 Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia. European journal of haematology 26 27743390
2022 G6b-B regulates an essential step in megakaryocyte maturation. Blood advances 25 35134123
2021 Targeting platelet inhibition receptors for novel therapies: PECAM-1 and G6b-B. Platelets 18 33646086
2012 An investigation of hierachical protein recruitment to the inhibitory platelet receptor, G6B-b. PloS one 18 23185356
2005 The cell surface receptor G6b, a member of the immunoglobulin superfamily, binds heparin. FEBS letters 15 15848171
2021 Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 11 33434328
2019 Case report of a novel MPIG6B gene mutation in a Chinese boy with pancytopenia and splenomegaly. Gene 10 31276734
2023 Treatment of congenital thrombocytopenia and decreased collagen reactivity in G6b-B-deficient mice. Blood advances 6 36269841
2022 A novel MPIG6B gene mutation in an adolescent girl with congenital thrombocytopenia and myelofibrosis. Current research in translational medicine 5 35940081
2022 ASXL2 mutated myelodysplastic syndrome in a novel germline G6b variant. Leukemia research reports 3 35330689
2007 G6b-B cell surface inhibitory receptor expression is highly restricted to CD4+ T-cells and induced by interleukin-4-activated STAT6 pathway. Human immunology 3 17678728
2025 Thrombocytopenia in myelofibrosis is characterized by inflammatory megakaryocytes with reduced G6B expression. Blood 2 40643151
2024 A Rare MPIG6B Gene Mutation in a Saudi Adolescent Male With Thrombocytopenia, Anemia, and Myelofibrosis: A Case Report. Cureus 2 38481905
2024 MPIG6B Gene-Related Myelofibrosis: A Rare Inherited Disease That Is Frequently Described in Arab Population. Avicenna journal of medicine 2 38694137
2024 G6b-B antibody-based cis-acting platelet receptor inhibitors (CAPRIs) as a new family of anti-thrombotic therapeutics. bioRxiv : the preprint server for biology 2 38798354
2026 MPIG6B-related thrombocytopenia and myelofibrosis: A case report. Annals of hematology 0 41838173

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