title: The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling.
abstract: The hepatic Ashwell-Morell receptor (AMR) can bind and remove desialylated platelets. Here we demonstrate that platelets become desialylated as they circulate and age in blood. Binding of desialylated platelets to the AMR induces hepatic expression of thrombopoietin (TPO) mRNA and protein, thereby regulating platelet production. Endocytic AMR controls TPO expression through Janus kinase 2 (JAK2) and the acute phase response signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro. Recognition of this newly identified physiological feedback mechanism illuminates the pathophysiology of platelet diseases, such as essential thrombocythemia and immune thrombocytopenia, and contributes to an understanding of the mechanisms of thrombocytopenia observed with JAK1/2 inhibition.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Grozovsky
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Antonija Jurak
authors.initials: AJ
authors.lastname: Begonja
authors.affiliation: Division of Pulmonary and Respiratory Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Liu
authors.affiliation: Division of Pulmonary and Respiratory Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Visner
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Hartwig
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hervé
authors.identifier: 0000000307889204
authors.initials: H
authors.lastname: Falet
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hoffmeister
mesh_terms: D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013920:Thrombocythemia, Essential / Q000235:genetics / Q000473:pathology; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism*
chemical_list: C546927:ASGR1 protein, human; D037263:Asialoglycoprotein Receptor; D050796:STAT3 Transcription Factor; D013926:Thrombopoietin; C507924:JAK2 protein, human; D053614:Janus Kinase 2