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Suppression of Normal and Malignant Kit Signaling by a Bispecific Antibody Linking Kit with CD300a¹

Ido Bachelet^*, Ariel Munitz^*, Beata Berent-Maoz^*, David Mankuta and Francesca Levi-Schaffer^2,*

^* Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem and Department of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem, Israel

Through its receptor Kit (CD117), stem cell factor (SCF) critically regulates human mast cell (MC) differentiation, survival, priming, and activation. The dominance of SCF in setting these parameters compels stringent contra-regulation to maintain a balanced MC phenotype. We have synthesized a library of bispecific Ab fragments to examine the effect of linking Kit with CD300a. In this study, we report that CD300a exerts a strong inhibitory effect on Kit-mediated SCF-induced signaling, consequently impairing MC differentiation, survival, and activation in vitro. This effect derives from Kit-mediated tyrosine phosphorylation of CD300a and recruitment of the SHIP-1 but not of SH2-containing protein phosphatase 1. CD300a inhibits the constitutive activation of the human leukemic HMC-1 cells but not their survival. Finally, CD300a abrogates the allergic reaction induced by SCF in a murine model of cutaneous anaphylaxis. Our findings highlight CD300a as a novel regulator of Kit in human MC and suggest roles for this receptor as a suppressor of Kit signaling in MC-related disorders.

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.

¹ This work was supported in part by The Israel Cancer Association (Grant B-20070043) and the Aimwell Charitable Trust (U.K.).

² Address correspondence and reprint requests to Dr. Francesca Levi-Schaffer, Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. E-mail address: fls{at}cc.huji.ac.il

³ Abbreviations used in this paper: MC, mast cell; SCF, Stem cell factor; SHP-1/2, Src homology 2 containing protein tyrosine phosphatase 1 or 2; SHIP-1, Src homology 2 containing inositol 5' phosphatase 1; LAT, linker for activation of T cells; PI, propidium iodide.