SEARCH:   Advanced

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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 12, 2008 Accepted July 10, 2008 Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells Clotilde Simon, Elisabetta Dondi, Amandine Chaix, Paulo de Sepulveda, Terrance J Kubiseski, Nadine Varin-Blank, and Laura Velazquez* Institut Cochin, Universite Paris Descartes, CNRS (UMR8104), Paris, France Inserm U567, Paris, France Inserm UMR891, Laboratoire d'Hematopoiese Moleculaire et Fonctionnelle, Marseille, France Department of Biology, York University, Toronto, Ontario, Canada * Corresponding author; email: laura.velazquez{at}inserm.fr. 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 transduced with different Lnk proteins, we demonstrated that Lnk down-regulates SCF-induced proliferation with attenuation of mitogen-activated protein kinase and c-jun N-terminal kinase signaling. Furthermore, we showed that Lnk-/- BMMCs displayed increased SCF-dependent migration compared to 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]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020