The specific aims of this proposal center around the interaction between two proteins which contribute to mechanisms of cellular control in neural tissues. Neurofibromin (NF), the product of the tumor suppressor gene, NF1; and the Stem Cell Factor/cKIT complex (SCF/KIT). NF has been identified as one of the GTPase activating proteins (GAP) and functions as a negative regulator of the ras signal transduction pathway. To date, the function identified for NF is acting as an inhibitor ras linked to cellular proliferation, in its capacity to convert p21ras(GTP) to p21ras(GDP). Increases in KIT have been shown to occur in some leukaemias. There is evidence that the tyrosine kinase protein KIT and its growth factor ligand SCF are expressed in a malignant human schwannoma cell line and several neurofibroma-derived cell lines; SCF/KIT may act as an autocrine growth loop promoting cellular growth and proliferation. Normal human Schwann cells do not produce detectable KIT. SCF and KIT are both present in cell lines derived from neurofibroma tissues. Their action in these cell lines remains to be determined, but it has been postulated that if SCF/KIT acts as an autocrine loop--and in the case of type 1 neurofibromatosis mutations in NF are also present-- both defective NF and induced SCF/KIT may act in concert to drive Schwann cells down an aberrant proliferative pathway towards tumorigenesis.
