SH2B3 (LNK) Mutations from Myeloproliferative Neoplasms Patients Have Mild Loss of Function Against Wild Type JAK2 and JAK2 V617F

Overview

Journal Br J Haematol

Specialty Hematology

Date 2013 Apr 18

PMID 23590807

Citations 10

Authors

Maya Koren-Michowitz

Sigal Gery

Takayuki Tabayashi

Dechen Lin

Rocio Alvarez

Arnon Nagler

H Phillip Koeffler

Affiliations

Soon will be listed here.

Abstract

Somatic point mutations in the PH domain of SH2B3 (LNK), an adaptor protein that is highly expressed in haematopoietic cells, were recently described in patients with myeloproliferative neoplasms. We studied the effect of these mutations on the JAK2 signalling pathway in cells expressing either wild type JAK2 or the JAK2 V617F mutation. Compared to wild type SH2B3, PH domain mutants have mild loss of function, with no evidence for a dominant-negative effect. Mutants retain binding capacity for JAK2, an established SH2B3 target, as well as for the adaptor proteins 14-3-3 and CBL. Our data suggest that the loss of SH2B3 inhibitory function conferred by the PH domain mutations is mild and may collaborate with JAK2 V617F and CBL mutations in order to promote either the development or the progression of myeloproliferative neoplasms.

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References

Bersenev A, Wu C, Balcerek J, Jing J, Kundu M, Blobel G . Lnk constrains myeloproliferative diseases in mice. J Clin Invest. 2010; 120(6):2058-69. PMC: 2877957. DOI: 10.1172/JCI42032. View

Oh S, Simonds E, Jones C, Hale M, Goltsev Y, Gibbs Jr K . Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood. 2010; 116(6):988-92. PMC: 2924231. DOI: 10.1182/blood-2010-02-270108. View

Roberts K, Morin R, Zhang J, Hirst M, Zhao Y, Su X . Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012; 22(2):153-66. PMC: 3422513. DOI: 10.1016/j.ccr.2012.06.005. View

Tong W, Lodish H . Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. J Exp Med. 2004; 200(5):569-80. PMC: 2212736. DOI: 10.1084/jem.20040762. View

Bersenev A, Wu C, Balcerek J, Tong W . Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2. J Clin Invest. 2008; 118(8):2832-44. PMC: 2447929. DOI: 10.1172/JCI35808. View

Sargin B, Choudhary C, Crosetto N, Schmidt M, Grundler R, Rensinghoff M . Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood. 2007; 110(3):1004-12. DOI: 10.1182/blood-2007-01-066076. View

Velazquez L, Cheng A, Fleming H, Furlonger C, Vesely S, Bernstein A . Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J Exp Med. 2002; 195(12):1599-611. PMC: 2193556. DOI: 10.1084/jem.20011883. View

Jiang J, Balcerek J, Rozenova K, Cheng Y, Bersenev A, Wu C . 14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and progenitor cells. J Clin Invest. 2012; 122(6):2079-91. PMC: 3366400. DOI: 10.1172/JCI59719. View

Jones A, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L . Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005; 106(6):2162-8. DOI: 10.1182/blood-2005-03-1320. View

10.

Pardanani A, Lasho T, Finke C, Hanson C, Tefferi A . Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia. 2007; 21(9):1960-3. DOI: 10.1038/sj.leu.2404810. View

11.

Huang X, Li Y, Tanaka K, Moore K, Hayashi J . Cloning and characterization of Lnk, a signal transduction protein that links T-cell receptor activation signal to phospholipase C gamma 1, Grb2, and phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 1995; 92(25):11618-22. PMC: 40453. DOI: 10.1073/pnas.92.25.11618. View

12.

Hurtado C, Erquiaga I, Aranaz P, Migueliz I, Garcia-Delgado M, Novo F . LNK can also be mutated outside PH and SH2 domains in myeloproliferative neoplasms with and without V617FJAK2 mutation. Leuk Res. 2011; 35(11):1537-9. DOI: 10.1016/j.leukres.2011.07.009. View

13.

Li Y, He X, Jakes S, Hayashi J . Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Src homology 2 domains that can inhibit T cell activation. J Immunol. 2000; 164(10):5199-206. DOI: 10.4049/jimmunol.164.10.5199. View

14.

Hu J, Hubbard S . Structural characterization of a novel Cbl phosphotyrosine recognition motif in the APS family of adapter proteins. J Biol Chem. 2005; 280(19):18943-9. DOI: 10.1074/jbc.M414157200. View

15.

Gueller S, Hehn S, Nowak V, Gery S, Serve H, Brandts C . Adaptor protein Lnk binds to PDGF receptor and inhibits PDGF-dependent signaling. Exp Hematol. 2011; 39(5):591-600. DOI: 10.1016/j.exphem.2011.02.001. View

16.

Pikman Y, Lee B, Mercher T, McDowell E, Ebert B, Gozo M . MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006; 3(7):e270. PMC: 1502153. DOI: 10.1371/journal.pmed.0030270. View

17.

Cross N . Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2011; 2011:208-14. DOI: 10.1182/asheducation-2011.1.208. View

18.

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

19.

Baxter E, Scott L, Campbell P, East C, Fourouclas N, Swanton S . Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365(9464):1054-61. DOI: 10.1016/S0140-6736(05)71142-9. View

20.

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