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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4039-4047. Prepublished online as a Blood First Edition Paper on August 27, 2008; DOI 10.1182/blood-2008-05-154849. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-05-154849v1 112/10/4039    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Simon, C. Articles by Velazquez, L. Search for Related Content PubMed PubMed Citation Articles by Simon, C. Articles by Velazquez, L. Related Collections Hematopoiesis and Stem Cells Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells Clotilde Simon1,2,*, Elisabetta Dondi1,2,*, Amandine Chaix3, Paulo de Sepulveda3, Terrance J. Kubiseski4, Nadine Varin-Blank1,2, and Laura Velazquez1,2 1 Institut Cochin, Université Paris Descartes, CNRS UMR8104, Paris, France; 2 Inserm U567, Paris, France; 3 Inserm UMR891, Laboratoire d'Hématopoïèse Moléculaire et Fonctionnelle, Marseille, France; and 4 Department of Biology, York University, Toronto, ON Stem cell factor (SCF) plays critical roles in proliferation, survival, migration, and function of hematopoietic progenitor and mast cells through binding to Kit receptor. Previous studies have implicated the adaptor protein Lnk as an important negative regulator of SCF signaling. However, the molecular mechanism underlying this regulation is unclear. Here, we showed that the Src homology 2 domain (SH2) of Lnk binds directly and preferentially to phosphorylated tyrosine 567 in Kit juxtamembrane domain. Using Lnk–/– bone marrow mast cells (BMMCs) transduced with different Lnk proteins, we demonstrated that Lnk down-regulates SCF-induced proliferation with attenuation of mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase signaling. Furthermore, we showed that Lnk–/– BMMCs displayed increased SCF-dependent migration compared with wild-type cells, revealing a novel Lnk-mediated inhibitory function. This correlated with enhanced Rac and p38 MAPK activation. Finally, we found that Lnk domains and carboxy-terminal tyrosine contribute differently to inhibition of in vitro expansion of hematopoietic progenitors. Altogether, our results demonstrate that Lnk, through its binding to Kit tyrosine 567, negatively modulates specific SCF-dependent signaling pathways involved in the proliferation and migration of primary hematopoietic cells. 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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