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Originally published In Press as doi:10.1074/jbc.M003655200 on August 3, 2000

J. Biol. Chem., Vol. 275, Issue 42, 33167-33175, October 20, 2000
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Engagement of the CrkL Adapter in Interleukin-5 Signaling in Eosinophils*

Jian DuDagger §, Yazan M. Alsayed§||, Feng XinDagger , Steven J. AckermanDagger **, and Leonidas C. Platanias||

From the Dagger  Department of Biochemistry and Molecular Biology and the  Section of Hematology-Oncology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612 and the || West Side Veterans Affairs Medical Center, Chicago, Illinois 60607

Interleukin-5 (IL-5) drives the terminal differentiation of myeloid progenitors to the eosinophil lineage; blocks eosinophil apoptosis; and primes eosinophils for enhanced functional activities in allergic, parasitic, and other eosinophil-associated diseases. Here we describe a novel signaling pathway activated by the IL-5 receptor in eosinophils involving the CrkL adapter protein. We determined whether IL-5 induces activation of CrkL and STAT5 in eosinophils using both the human eosinophil-differentiated AML14.3D10 cell line and purified peripheral blood eosinophils from normal donors. Stimulation of AML14.3D10 cells or blood eosinophils with IL-5 induced rapid tyrosine phosphorylation of the CrkL adapter and STAT5 and the association of CrkL and STAT5 in vivo as evidenced by the detection of STAT5 in anti-CrkL immunoprecipitates. The resulting CrkL·STAT5 complexes translocated to the nucleus and bound STAT5 consensus DNA-binding sites present in the promoters of IL-5-regulated genes, as shown in gel mobility and antibody supershift assays. IL-5 also induced marked activity of an 8X-GAS (interferon gamma -activated site)-luciferase reporter construct in transient transfections of AML14.3D10 eosinophils, demonstrating that these complexes play a functional role in IL-5 signaling. CrkL was also found to interact, via its N-terminal SH3 domain, with C3G, a guanine exchange factor for the small G-protein Rap1, which was also rapidly activated in an IL-5-dependent manner in these cells, establishing that CrkL mediates downstream activation of at least two signaling cascades in IL-5-stimulated eosinophils. Thus, the CrkL adapter plays an important role in IL-5 signaling in the eosinophil, acting as a nuclear adapter for STAT5 and as an upstream regulator of the C3G-Rap1 signaling pathway.

* This work was supported by Grants AI33043 and AI25230 (to S. J. A.) and Grants CA77816 and CA73381 (to L. C. P.) from the National Institutes of Health and by a Merit Review grant from the Department of Veterans Affairs (to L. C. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work as joint first authors.

** To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, A-312 College of Medicine West, MC536, University of Illinois, 1819 West Polk St., Chicago, IL 60612. Tel.: 312-996-6149; Fax: 312-996-5623; E-mail: sackerma@uic.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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