The receptor tyrosine kinases KIT and FLT3 are both important regulators of development and maintenance of a number of different cell types. Deregulation of these tyrosine kinases by mutations has been implicated in various human malignancies, including leukemia and melanoma. The signaling pathways activated by the oncogenic mutants are in part overlapping with those normally activated by these receptors, but there are also signal transduction pathways that are unique to the oncogenic mutants. These molecules are potential novel targets for pharmacological intervention. The aim of this project is to elucidate the mechanism of signal transduction of the oncogenic mutants of FLT3 and KIT and find such molecules.
By a broad mass spectrometry based approach on whole cells we are in the process of identifying additional such proteins and their phosphorylation status. Finally, patients with certain subtypes of malignant melanoma carry activating mutations in KIT that is driving the disease. Given the functional relation between KIT and the transcription factor MITF, we are investigating the molecular mechanisms behind the KIT-mediated regulation of MITF.