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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4604-4612. Prepublished online as a Blood First Edition Paper on February 10, 2005; DOI 10.1182/blood-2004-10-4093. This Article Full Text (PDF) All Versions of this Article: 2004-10-4093v1 105/12/4604    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 Tong, W. Articles by Lodish, H. F Search for Related Content PubMed PubMed Citation Articles by Tong, W. Articles by Lodish, H. F Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 25, 2004 Accepted February 4, 2005 Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways Wei Tong, Jing Zhang, and Harvey F Lodish* Whitehead Institute for Biomedical Research, Cambridge, MA, USA Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA * Corresponding author; email: lodish{at}wi.mit.edu. Erythropoietin (Epo), along with its receptor EpoR, is the principal regulator of red cell development. Upon Epo addition, the EpoR signaling the JAK2 tyrosine kinase, activates multiple pathways including Stat5, PI-3K/Akt, and p42/44MAPK. The adaptor protein Lnk is implicated in cytokine receptor signaling. Here, we showed that Lnk-deficient mice have elevated numbers of erythroid progenitors, and that splenic CFU-e progenitors are hypersensitive to Epo. Lnk-/- mice also exhibit superior recovery after erythropoietic stress. In addition, Lnk deficiency resulted in enhanced Epo-induced signaling pathways in splenic erythroid progenitors. Conversely, Lnk overexpression inhibits Epo-induced cell growth in 32D/EpoR cells. In primary culture of fetal liver cells, Lnk overexpression inhibits Epo-dependent erythroblast differentiation and induces apoptosis. Lnk blocks three major signaling pathways, Stat5, Akt, and MAPK, induced by Epo in primary erythroblasts. In addition, the Lnk SH2 domain is essential for its inhibitory function, whereas the conserved tyrosine near the C-terminus and the PH domain of Lnk are not critical. Furthermore, wild type Lnk, but not the Lnk SH2 mutant, becomes tyrosine-phosphorylated following Epo administration and inhibits EpoR phosphorylation and JAK2 activation. Hence, Lnk, through its SH2 domain, negatively modulates EpoR signaling by attenuating JAK2 activation, and regulates Epo-mediated erythropoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. L. Morris, K. W. Cho, Y. Zhou, and L. Rui SH2B1 Enhances Insulin Sensitivity by Both Stimulating the Insulin Receptor and Inhibiting Tyrosine Dephosphorylation of Insulin Receptor Substrate Proteins Diabetes, September 1, 2009; 58(9): 2039 - 2047. [Abstract] [Full Text] [PDF] 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] O. Bogacheva, O. Bogachev, M. Menon, A. Dev, E. Houde, E. I. Valoret, H. M. Prosser, C. L. Creasy, S. J. Pickering, E. Grau, et al. DYRK3 Dual-specificity Kinase Attenuates Erythropoiesis during Anemia J. Biol. 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