Lnk Controls Mouse Hematopoietic Stem Cell Self-renewal and Quiescence Through Direct Interactions with JAK2

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2008 Jul 12

PMID 18618018

Citations 110

Authors

Alexey Bersenev

Chao Wu

Joanna Balcerek

Wei Tong

Affiliations

Soon will be listed here.

Abstract

In addition to its role in megakaryocyte production, signaling initiated by thrombopoietin (TPO) activation of its receptor, myeloproliferative leukemia virus protooncogene (c-Mpl, or Mpl), controls HSC homeostasis and self-renewal. Under steady-state conditions, mice lacking the inhibitory adaptor protein Lnk harbor an expanded HSC pool with enhanced self-renewal. We found that HSCs from Lnk-/- mice have an increased quiescent fraction, decelerated cell cycle kinetics, and enhanced resistance to repeat treatments with cytoablative 5-fluorouracil in vivo compared with WT HSCs. We further provide genetic evidence demonstrating that Lnk controls HSC quiescence and self-renewal, predominantly through Mpl. Consistent with this observation, Lnk-/- HSCs displayed potentiated activation of JAK2 specifically in response to TPO. Biochemical experiments revealed that Lnk directly binds to phosphorylated tyrosine residues in JAK2 following TPO stimulation. Of note, the JAK2 V617F mutant, found at high frequencies in myeloproliferative diseases, retains the ability to bind Lnk. Therefore, we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence.

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References

Kimura S, Roberts A, Metcalf D, Alexander W . Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc Natl Acad Sci U S A. 1998; 95(3):1195-200. PMC: 18717. DOI: 10.1073/pnas.95.3.1195. View

Parganas E, Wang D, Stravopodis D, Topham D, Marine J, Teglund S . Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998; 93(3):385-95. DOI: 10.1016/s0092-8674(00)81167-8. View

Levine R, Wadleigh M, Cools J, Ebert B, Wernig G, Huntly B . Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005; 7(4):387-97. DOI: 10.1016/j.ccr.2005.03.023. View

Kaushansky K . Thrombopoietin: a tool for understanding thrombopoiesis. J Thromb Haemost. 2003; 1(7):1587-92. DOI: 10.1046/j.1538-7836.2003.00273.x. View

Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K . Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004; 118(2):149-61. DOI: 10.1016/j.cell.2004.07.004. View

Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y . Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2008; 1(6):685-97. DOI: 10.1016/j.stem.2007.10.020. View

Qian H, Buza-Vidas N, Hyland C, Jensen C, Antonchuk J, Mansson R . Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell. 2008; 1(6):671-84. DOI: 10.1016/j.stem.2007.10.008. View

Huang L, Constantinescu S, Lodish H . The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cell. 2002; 8(6):1327-38. DOI: 10.1016/s1097-2765(01)00401-4. View

Wilson A, Murphy M, Oskarsson T, Kaloulis K, Bettess M, Oser G . c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004; 18(22):2747-63. PMC: 528895. DOI: 10.1101/gad.313104. View

10.

Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A . c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood. 2001; 97(1):139-46. DOI: 10.1182/blood.v97.1.139. View

11.

Krutzik P, Nolan G . Intracellular phospho-protein staining techniques for flow cytometry: monitoring single cell signaling events. Cytometry A. 2003; 55(2):61-70. DOI: 10.1002/cyto.a.10072. View

12.

Constantinescu S, Huang L, Nam H, Lodish H . The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif. Mol Cell. 2001; 7(2):377-85. DOI: 10.1016/s1097-2765(01)00185-x. View

13.

James C, Ugo V, Le Couedic J, Staerk J, Delhommeau F, Lacout C . A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005; 434(7037):1144-8. DOI: 10.1038/nature03546. View

14.

Harrison D, Astle C . Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure. J Exp Med. 1982; 156(6):1767-79. PMC: 2186863. DOI: 10.1084/jem.156.6.1767. View

15.

Drachman J, Kaushansky K . Structure and function of the cytokine receptor superfamily. Curr Opin Hematol. 1995; 2(1):22-8. DOI: 10.1097/00062752-199502010-00004. View

16.

Yuan Y, Shen H, Franklin D, Scadden D, Cheng T . In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat Cell Biol. 2004; 6(5):436-42. DOI: 10.1038/ncb1126. View

17.

Gurney A, de Sauvage F, Moore M . Thrombocytopenia in c-mpl-deficient mice. Science. 1994; 265(5177):1445-7. DOI: 10.1126/science.8073287. View

18.

de Sauvage F, Luoh S, Ryan A, Dowd M, Eaton D, Moore M . Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med. 1996; 183(2):651-6. PMC: 2192470. DOI: 10.1084/jem.183.2.651. View

19.

Hock H, Hamblen M, Rooke H, Schindler J, Saleque S, Fujiwara Y . Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature. 2004; 431(7011):1002-7. DOI: 10.1038/nature02994. View

20.

Takaki S, Sauer K, Iritani B, Chien S, Ebihara Y, Tsuji K . Control of B cell production by the adaptor protein lnk. Definition Of a conserved family of signal-modulating proteins. Immunity. 2000; 13(5):599-609. PMC: 5291696. DOI: 10.1016/s1074-7613(00)00060-1. View