BBB seminar: Lars Rönnstrand
Signaling through the receptor for stem cell factor/c-Kit in normal and transformed cells: a central role for Src family kinases
Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Sweden
The stem cell factor receptor/c-Kit has a normal physiological function in the development of germ cells, hematopoiesis and melanogenesis. Aberrant deregulation of c-Kit has been found in a number of different human malignancies, including small cell lung carcinoma, gastrointestinal stromal tumors, acute myeloid leukemia (AML) and testicular carcinoma. One of the most common mutations found in both AML and testicular carcinomas is a mutation of D816 to either V, H or Y. D816 resides in the activation loop of the tyrosine kinase domain of c-Kit.
The aim of our project is to understand on the molecular level how c-Kit signals and to investigate the sometimes unique properties of the oncogenic mutants of c-Kit. We have found that major differences between two alternative splice forms of c-Kit lie in their differential activation of Src families which in turn leads to differences in downstream signaling.
Apart from being directly involved in transformation of cells, activation of c-Kit also leads to stabilization of the transcription factor HIF1alpha, which leads to the induction under normoxia of a number of hypoxia-inducible genes. The implication of this gene regulation will be discussed.
Host: Donald Gullberg, Department of Biomedicine