c-Kit-mediated overlapping and unique functional and biochemical outcomes via diverse signaling pathways |
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Authors: | Hong Li Munugalavadla Veerendra Kapur Reuben |
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Institution: | Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. |
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Abstract: | 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. |
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