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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3360-3364. Prepublished online as a Blood First Edition Paper on August 10, 2007; DOI 10.1182/blood-2007-05-089326. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-05-089326v1 110/9/3360    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gery, S. Articles by Koeffler, H P. Search for Related Content PubMed PubMed Citation Articles by Gery, S. Articles by Koeffler, H P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 8, 2007 Accepted August 3, 2007 Adaptor protein Lnk, negatively regulates the mutant MPL, MPLW515L, associated with myeloproliferative disorders Sigal Gery*, Saskia Gueller, Katya Chumakova, Norihiko Kawamata, Liqin Liu, and H Phillip Koeffler Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States Division of Hematology/Oncology, Amgen, Thousand Oaks, CA, United States * Corresponding author; email: gerys{at}cshs.org. Recently, activating MPL mutations, MPLW515L/K, were described in myeloproliferative disorders (MPD) patients. MPLW515L leads to activation of downstream signaling pathways and cytokine-independent proliferation in hematopoietic cells. The adaptor protein Lnk is a negative regulator of several cytokine receptors including MPL. We show that overexpression of Lnk in Ba/F3-MPLW515L cells inhibits cytokine-independent growth, while suppression of Lnk in UT7-MPLW515L cells enhances proliferation. Lnk blocks the activation of Jak2, Stat3, Erk and Akt in these cells. Furthermore, MPLW515L expressing cells are more susceptible to Lnk inhibitory functions than their MPL wild type (MPLWT)-expressing counterparts. Lnk associates with activated MPLWT and MPLW515L and co-localizes with the receptors at the plasma membrane. The SH2 domain of Lnk is essential for its binding and for its downregulation of MPLWT and MPLW515L. Lnk itself is tyrosine-phosphorylated following thrombopoietin stimulation. Further elucidating the cellular pathways that attenuate MPLW515L will provide insight into the pathogenesis of MPD and could help develop specific therapeutic approaches. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Gery, Q. Cao, S. Gueller, H. Xing, A. Tefferi, and H. P. Koeffler Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F J. Leukoc. Biol., June 1, 2009; 85(6): 957 - 965. [Abstract] [Full Text] [PDF]

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