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J. Biol. Chem., Vol. 279, Issue 7, 5612-5620, February 13, 2004

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Tumor Necrosis Factor--converting Enzyme Controls Surface Expression of c-Kit and Survival of Embryonic Stem Cell-derived Mast Cells^*

Anthony C. Cruz, Brendon T. Frank, Samuel T. Edwards, Paul F. Dazin, Jacques J. Peschon, and Kenneth C. Fang¶||**

From the ^¶Cardiovascular Research Institute, ^||Department of Medicine, and Howard Hughes Medical Institute, University of California, San Francisco, California 94143 and Amgen Inc., Seattle, Washington 98101

Transmembrane metalloproteinases of the disintegrin and metalloproteinase (ADAM) family control cell signaling interactions via hydrolysis of protein extracellular domains. Prior work has shown that the receptor tyrosine kinase, c-Kit (CD117), is essential for mast cell survival and that serum levels of c-Kit increase in proliferative mast cell disorders, suggesting the existence of c-Kit shedding pathways in mast cells. In the present work, we report that tumor necrosis factor -converting enzyme (TACE; ADAM-17) mediates shedding of c-Kit. Stimulation of transfected cells with phorbol 12-myristate 13-acetate (PMA) induced metalloproteinase-mediated release of c-Kit ectodomain, which increased further upon TACE overexpression. By contrast, TACE-deficient fibroblasts did not demonstrate inducible release, thus identifying TACE as the metalloproteinase primarily responsible for PMA-induced c-Kit shedding. Surface expression of c-Kit by the human mast cell-1 line decreased upon phorbol-induced shedding, which involved metalloproteinase activity susceptible to inhibition by tissue inhibitor of metalloproteinase (TIMP)-3. To further explore the role of TACE in shedding of c-Kit from mast cells, we compared the behavior of mast cells derived from murine embryonic stem cells. In these studies, PMA decreased surface c-Kit levels on mast cells expressing wild-type (+/+) TACE but not on those expressing an inactive mutant (Zn/Zn), confirming the role of TACE in PMA-induced c-Kit shedding. Compared with TACE^+/+ cells, TACE^Zn/Zn mast cells also demonstrated decreased constitutive shedding and increased basal surface expression of c-Kit, with diminished apoptosis in response to c-Kit ligand deprivation. These data suggest that TACE controls mast cell survival by regulating shedding and surface expression of c-Kit.

Received for publication, November 11, 2003

^* This work was supported by National Institutes of Health Grant HL-64897, a research award from the American Lung Association of California, an American Lung Association Career Investigator Award, and a research grant from the Research Evaluation and Allocation Committee of the University of California, San Francisco School of Medicine. 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: Box 0911, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0911. Tel.: 415-502-7938; Fax: 415-476-9749; E-mail: kfang{at}itsa.ucsf.edu.

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