Although the NF1 and NF2 candidate tumor suppressor genes have been implicated in the development of neurofibromatosis type 1 and 2, respectively, the precise functions of their encoded proteins remain to be elucidated. NF1 encodes neurofibromin, which has been shown to function as a GTPase activating protein (GAP) for the Ras proto-oncogene proteins. However, there is also evidence that neurofibromin may mediate downstream effector signaling pathways that promote Ras regulation of cellular differentiation.

Whether neurofibromin is an effector of Ras remains to be determined. NF2 encodes merlin, a member of the ERM family of proteins that is believed to function in linking cytoskeletal components with membrane proteins. However, little is known concerning merlin function. Like neurofibromin, merlin expression has been shown to antagonize Ras transformation. However, how either protein blocks Ras transformation remains poorly understood.

Farnesyltransferase inhibitors (FTIs) have been shown to be potent inhibitors of Ras transformation and are promising drugs for cancer treatment. FTI treatment has also been shown to be effective in blocking the transformed growth of an NF1-deficient malignant schwannoma cell line that exhibits upregulated Ras activity. However, whether FTIs will be effective inhibitors of the majority of NF1-deficient tumors and whether they will be useful for the treatment of NF2-deficient tumors has not been established.

Three specific aims are proposed to evaluate the function of neurofibromin and merlin. These studies will emphasize the relationship between Ras signaling and transformation and the tumor suppressing action of these two proteins. Specific Aim 1 will evaluate the possible role of neurofibromin as an effector for Ras signaling pathways that control cellular differentiation. Specific Aim 2 will determine if FTIs are inhibitors of cells that are deficient in neurofibromin and merlin expression.

Specific Aim 3 will determine if merlin antagonizes Ras transformation by antagonizing Rho protein deregulation of actin cytoskeleton organization. Taken together, these studies will contribute to our understanding of neurofibromin and merlin function. Furthermore, elucidating the mechanisms by which neurofibromin and merlin antagonize Ras transformation may define Ras signaling components that represent novel targets for the treatment of NF1- and NF2-associated human malignancies.