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

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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.

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