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Molecular and Cellular Biology, February 2004, p. 1401-1410, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1401-1410.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

c-Kit-Mediated Overlapping and Unique Functional and Biochemical Outcomes via Diverse Signaling Pathways

Li Hong, Veerendra Munugalavadla, and Reuben Kapur*

Department of Pediatrics, Herman B. Wells Center for Pediatric Research, and Department of Molecular Biology and Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202

Received 7 July 2003/ Returned for modification 18 August 2003/ Accepted 3 November 2003

A critical issue in understanding receptor tyrosine kinase signaling is the individual contribution of diverse signaling pathways in regulating cellular growth, survival, and migration. We generated a functionally and biochemically inert c-Kit receptor that lacked the binding sites for seven early signaling pathways. Restoring the Src family kinase (SFK) binding sites in the mutated c-Kit receptor restored cellular survival and migration but only partially rescued proliferation and was associated with the rescue of the Ras/mitogen-activated protein kinase, Rac/JNK kinase, and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt pathways. In contrast, restoring the PI-3 kinase binding site in the mutated receptor did not affect cellular proliferation but resulted in a modest correction in cell survival and migration, despite a complete rescue in the activation of the PI-3 kinase/Akt pathway. Surprisingly, restoring the binding sites for Grb2, Grb7, or phospholipase C-{gamma} had no effect on cellular growth or survival, migration, or activation of any of the downstream signaling pathways. These results argue that SFKs play a unique role in the control of multiple cellular functions and in the activation of distinct biochemical pathways via c-Kit.

* Corresponding author. Mailing address: Herman B. Wells Center for Pediatric Research, Cancer Research Building, 1044 W. Walnut St., Room 425, Indianapolis, IN 46202. Phone: (317) 278-0543. Fax: (317) 274-8679. E-mail: rkapur{at}iupui.edu.

Molecular and Cellular Biology, February 2004, p. 1401-1410, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1401-1410.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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