HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 43, 44544-44553, October 22, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/43/44544    most recent M404085200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lennartsson, J. Articles by Linnekin, D. Search for Related Content PubMed PubMed Citation Articles by Lennartsson, J. Articles by Linnekin, D. Social Bookmarking                      What's this?

Synergistic Growth of Stem Cell Factor and Granulocyte Macrophage Colony-stimulating Factor Involves Kinase-dependent and -independent Contributions from c-Kit^*

Johan Lennartsson, R. Shivakrupa, and Diana Linnekin

From the Basic Research Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702

Stem cell factor (SCF) binds and activates the receptor tyrosine kinase c-Kit, and this interaction is critical for normal hematopoiesis. SCF also synergizes with a variety of growth factors, including those binding members of the cytokine receptor superfamily. The mechanisms mediating this synergy remain to be defined. The present study investigates both structural and biochemical cross-talk between c-Kit and the receptor for granulocyte macrophage colony-stimulating factor (GM-CSF). We have found that c-Kit forms a complex with the -chain of the GM-CSF receptor, and this interaction involves the first part of the c-Kit kinase domain. Although inhibition of c-Kit kinase activity completely blocked SCF-induced proliferation, there was still greater than additive growth induced by SCF in combination with GM-CSF. In contrast, an inhibitory antibody against the extracellular domain of c-Kit (K-27) completely inhibited growth in response to SCF alone or in combination with GM-CSF. These results support a kinase-independent component of the synergistic growth induced by SCF and GM-CSF that may relate to interaction of these receptors. It is also clear that a significant part of the synergistic growth is dependent of c-Kit kinase activity. Although synergistic increases in phosphorylation of c-Kit and the -chain of the GM-CSF receptor were not observed, SCF and GM-CSF in combination prolonged the duration of Erk1/2 phosphorylation in a phosphatidylinositol 3-kinase-dependent manner. Consistent with these findings, phosphatidylinositol 3-kinase is synergistically activated by SCF and GM-CSF together. Hence, c-Kit makes both kinase-independent and -dependent contributions to the proliferative synergy induced by SCF in combination with GM-CSF.

Received for publication, April 13, 2004 , and in revised form, August 4, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Ludwig Institute for Cancer Research, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden. Tel.: 46-18-160406; Fax: 46-18-160420; E-mail: Johan.Lennartsson{at}LICR.uu.se.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. M. Benson Jr, J. Yu, B. Becknell, M. Wei, A. G. Freud, A. K. Ferketich, R. Trotta, D. Perrotti, R. Briesewitz, and M. A. Caligiuri Stem cell factor and interleukin-2/15 combine to enhance MAPK-mediated proliferation of human natural killer cells Blood, March 19, 2009; 113(12): 2706 - 2714. [Abstract] [Full Text] [PDF]

				S. Ito, C. R. Mantel, M.-K. Han, S. Basu, S. Fukuda, S. Cooper, and H. E. Broxmeyer Mad2 is required for optimal hematopoiesis: Mad2 associates with c-Kit in MO7e cells Blood, March 1, 2007; 109(5): 1923 - 1930. [Abstract] [Full Text] [PDF]

				L. S. Haneline, H. White, F.-C. Yang, S. Chen, C. Orschell, R. Kapur, and D. A. Ingram Genetic reduction of class IA PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo Blood, February 15, 2006; 107(4): 1375 - 1382. [Abstract] [Full Text] [PDF]

				Z.-j. Ye, Y. Kluger, Z. Lian, and S. M. Weissman Two types of precursor cells in a multipotential hematopoietic cell line PNAS, December 20, 2005; 102(51): 18461 - 18466. [Abstract] [Full Text] [PDF]