The Ashwell-Morell Receptor Regulates Hepatic Thrombopoietin Production Via JAK2-STAT3 Signaling

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2014 Dec 9

PMID 25485912

Citations 133

Authors

Renata Grozovsky

Antonija Jurak Begonja

Kaifeng Liu

Gary Visner

John H Hartwig

Herve Falet

Karin M Hoffmeister

Affiliations

Soon will be listed here.

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.

Citing Articles

The function of T cells in immune thrombocytopenia.

Bu S, Liu M, Yang L, Lee P, Miller H, Park C Front Immunol. 2025; 16:1499014.

PMID: 40061938 PMC: 11885273. DOI: 10.3389/fimmu.2025.1499014.

Impact of Thrombopoietin Receptor Agonists on Pathophysiology of Pediatric Immune Thrombocytopenia.

Evangelidis P, Tragiannidis K, Gavriilaki E, Tragiannidis A Curr Issues Mol Biol. 2025; 47(1).

PMID: 39852180 PMC: 11763769. DOI: 10.3390/cimb47010065.

Desialylation and Apoptosis in Immune Thrombocytopenia: Implications for Pathogenesis and Treatment.

Zheng S, Perdomo J Curr Issues Mol Biol. 2024; 46(11):11942-11956.

PMID: 39590303 PMC: 11592706. DOI: 10.3390/cimb46110709.

LMAN1 serves as a cargo receptor for thrombopoietin.

Everett L, Lin Z, Friedman A, Tang V, Myers G, Balbin-Cuesta G JCI Insight. 2024; 9(24).

PMID: 39499573 PMC: 11665562. DOI: 10.1172/jci.insight.175704.

Discovery of an unconventional lamprey lymphocyte lineage highlights divergent features in vertebrate adaptive immune system evolution.

Huang Y, Liu X, Li S, Li C, Wang H, Liu Q Nat Commun. 2024; 15(1):7626.

PMID: 39227584 PMC: 11372201. DOI: 10.1038/s41467-024-51763-2.

References

Shinjo K, Takeshita A, Nakamura S, Naitoh K, Yanagi M, Tobita T . Serum thrombopoietin levels in patients correlate inversely with platelet counts during chemotherapy-induced thrombocytopenia. Leukemia. 1998; 12(3):295-300. DOI: 10.1038/sj.leu.2400946. View

LaFave L, Levine R . JAK2 the future: therapeutic strategies for JAK-dependent malignancies. Trends Pharmacol Sci. 2012; 33(11):574-82. DOI: 10.1016/j.tips.2012.08.005. View

Qian S, Fu F, Li W, Chen Q, de Sauvage F . Primary role of the liver in thrombopoietin production shown by tissue-specific knockout. Blood. 1998; 92(6):2189-91. View

Griesshammer M, Hornkohl A, Nichol J, Hecht T, Raghavachar A, Heimpel H . High levels of thrombopoietin in sera of patients with essential thrombocythemia: cause or consequence of abnormal platelet production?. Ann Hematol. 1998; 77(5):211-5. DOI: 10.1007/s002770050445. View

Vitrat N, Titeux M, Vainchenker W, Wendling F . High-level expression of Mpl in platelets and megakaryocytes is independent of thrombopoietin. Blood. 1999; 93(9):2859-66. View

Engel C, Loeffler M, Franke H, Schmitz S . Endogenous thrombopoietin serum levels during multicycle chemotherapy. Br J Haematol. 1999; 105(3):832-8. DOI: 10.1046/j.1365-2141.1999.01459.x. View

Mouthon M, Vandamme M, Gourmelon P, Vainchenker W, Wendling F . Preferential liver irradiation enhances hematopoiesis through a thrombopoietin-independent mechanism. Radiat Res. 1999; 152(4):390-7. View

Kaushansky K . The molecular mechanisms that control thrombopoiesis. J Clin Invest. 2005; 115(12):3339-47. PMC: 1297257. DOI: 10.1172/JCI26674. View

Mason K, Carpinelli M, Fletcher J, Collinge J, Hilton A, Ellis S . Programmed anuclear cell death delimits platelet life span. Cell. 2007; 128(6):1173-86. DOI: 10.1016/j.cell.2007.01.037. View

10.

Zhang H, Nimmer P, Tahir S, Chen J, Fryer R, Hahn K . Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 2007; 14(5):943-51. DOI: 10.1038/sj.cdd.4402081. View

11.

Grewal P, Uchiyama S, Ditto D, Varki N, Le D, Nizet V . The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat Med. 2008; 14(6):648-55. PMC: 2853759. DOI: 10.1038/nm1760. View

12.

McIntosh B, Kaushansky K . Transcriptional regulation of bone marrow thrombopoietin by platelet proteins. Exp Hematol. 2008; 36(7):799-806. PMC: 2517608. DOI: 10.1016/j.exphem.2008.02.012. View

13.

Levine R, Gilliland D . Myeloproliferative disorders. Blood. 2008; 112(6):2190-8. PMC: 2962533. DOI: 10.1182/blood-2008-03-077966. View

14.

Grozovsky R, Ribich S, Rosene M, Mulcahey M, Huang S, Patti M . Type 2 deiodinase expression is induced by peroxisomal proliferator-activated receptor-gamma agonists in skeletal myocytes. Endocrinology. 2008; 150(4):1976-83. PMC: 2659265. DOI: 10.1210/en.2008-0938. View

15.

Kuter D . Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med. 2009; 60:193-206. DOI: 10.1146/annurev.med.60.042307.181154. View

16.

Sorensen A, Rumjantseva V, Nayeb-Hashemi S, Clausen H, Hartwig J, Wandall H . Role of sialic acid for platelet life span: exposure of beta-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor-expressing liver macrophages and hepatocytes. Blood. 2009; 114(8):1645-54. PMC: 2731641. DOI: 10.1182/blood-2009-01-199414. View

17.

Rumjantseva V, Grewal P, Wandall H, Josefsson E, Sorensen A, Larson G . Dual roles for hepatic lectin receptors in the clearance of chilled platelets. Nat Med. 2009; 15(11):1273-80. PMC: 4428152. DOI: 10.1038/nm.2030. View

18.

Grewal P . The Ashwell-Morell receptor. Methods Enzymol. 2010; 479:223-41. DOI: 10.1016/S0076-6879(10)79013-3. View

19.

Park S, Wamsley H, Bae K, Hu Z, Li X, Choe S . Conditional deletion of Jak2 reveals an essential role in hematopoiesis throughout mouse ontogeny: implications for Jak2 inhibition in humans. PLoS One. 2013; 8(3):e59675. PMC: 3609865. DOI: 10.1371/journal.pone.0059675. View

20.

Grewal P, Aziz P, Uchiyama S, Rubio G, Lardone R, Le D . Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor. Proc Natl Acad Sci U S A. 2013; 110(50):20218-23. PMC: 3864324. DOI: 10.1073/pnas.1313905110. View