Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor

Mutations in the NF1 tumor suppressor underlie the familial tumor predisposition syndrome neurofibromatosis type I. Although its encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (GAP), nothing is known about how it is normally regulated or its precise role in controlling Ras signaling pathways. We show here that neurofibromin is dynamically regulated by the ubiquitin-proteasome pathway. Degradation is rapidly triggered in response to a variety of growth factors and requires sequences adjacent to the catalytic GAP-related domain of neurofibromin. However, whereas degradation is rapid, neurofibromin levels are re-elevated shortly after growth factor treatment. Accordingly, Nf1-deficient mouse embryonic fibroblasts (MEFs) exhibit an enhanced activation of Ras, prolonged Ras and ERK activities, and proliferate in response to subthreshold levels of growth factors. Thus, the dynamic proteasomal regulation of neurofibromin represents an important mechanism of controlling both the amplitude and duration of Ras-mediated signaling. Furthermore, this previously unrecognized Ras regulatory mechanism may be exploited therapeutically.