Distinctive role of the cKit receptor tyrosine kinase signaling in mammalian melanocytes

The cKit receptor plays a critical role in melanocyte physiology, influencing melanogenesis, proliferation, migration, and survival of the pigment-producing cells. However, pathways of cKit-mediated intracellular signaling and molecular mechanisms, which regulate specific cellular responses to the activation of the receptor in melanocytes, remain incompletely understood. Here, by using the genetically altered mouse melanocytes expressing an endogenous, constitutively active mutant (D814Y) cKit receptor, we investigated physiological cellular responses to the ligand-independent activation of the receptor tyrosine kinase. It was anticipated that such activation would either trigger uncontrolled proliferation of the melanocytes or stimulate melanin biosynthesis. In contrast to the expectation, we found that constitutive signaling from the cKit receptor did not stimulate melanogenesis and proliferation, but significantly promoted migration of the melanocytes both in vitro and in vivo. We also showed that such signaling is not associated with tumorigenic transformation of the pigment-producing cells. Taken together, our observations suggest that, in mammalian melanocytes, activation of the cKit receptor tyrosine kinase is primarily responsible for transmission of pro-migration signals, which may antagonize proliferation and melanogenesis. Our data also provide an additional explanation as to why malignant melanocytes lose cKit expression during melanoma progression.