Tumor cell linesderivedfrom malignant schwannomas removed from patients with neurofibromatosis type 1 (NFl) have been examined for the level of expression of NFl protein. All three NFl linesexaminedexpressed lower levels of NFl protein than control cells, and the level in one line was barely detectable. The tumor lines expressed normal levels of p120wp and~ 21’~. Although the p21 I” proteins isolated from the tumor cells had normal (nonmutant) biochemical properties in vitro, they displayed elevated levels of bound GTP in vivo. The level of total cellular GAP-like activity was reduced in extracts from the tumor line that expresses very little NFl protein. Introduction of the catalytic region of GAP into this line resulted in morphological reversion and lower in vivo GTP binding by endogenous~ 21”~. These data implicate NFl protein as a tumor suppressor gene product that negatively regulates~ 21” and define a ‘positive” growth role for ras activity in NFl malignancies.