Abstract Neurofibromatosis type 1 (NF1) patients are predisposed to develop neurofibromas, benign peripheral nerve tumors resulting from loss of function mutations in the NF1 gene. NF1 (neurofibromin), the protein product of the NF1 gene, is a GTPase activating protein (GAP) that inactivates the Ras proteins H-, N-, K-, M-, and R-Ras, and R-Ras2/TC21 (TC21). We hypothesized that relevant Ras proteins would be activated in vivo by deletion of NF1, so that removing single Ras proteins in Nf1 mutant cells would reveal specific functions of individual Ras proteins. We found that activation of TC21 accounts for migration defects in NF1 mutant Schwann cells (Huang et al, 2004), through AKT and not ERK. Removing TC21 in Nf1 mutant Schwann cell precursors identified an Nf1/TGFβ/TGFβRII/AKT autocrine survival loop (Patmore et al, 2012). Implying that delayed benign tumor formation resulted from effects on tumor initiation, benign tumor formation was delayed in mice lacking Nf1 and TC21. In Schwann cell precursors, activation of P-ERK, not P-AKT, was blocked by dnH-Ras. To define the role of ERK signaling in neurofibroma, we used a DhhCre;Nf1fl/fl mouse model of neurofibroma formation. Preclinical testing of specific signaling pathways with Phase I drug candidates in the neurofibroma mouse model was read out neurofibroma growth by 7T MRI imaging, in conjunction with pharmacokinetic and pharmacodynamic readouts (Jessen et al., 2013). MEK inhibition was highly effective although not curative in this model; we established minimum effective doses of the MEK inhibitor PD0325901 and effects of early MEK inhibition on peripheral nerve tumor growth. The data support the idea that NF1 GAP loss can be used to identify roles of individual Ras proteins and downstream signaling pathways in specific cell types, and that combinations of Ras proteins can collaborate to drive tumorigenesis. Supported by R01-NS28840, P50-NS057531 and the Children's Tumor Foundation/ Neurofibromatosis Therapeutic Acceleration Program. Citation Format: Nancy Ratner. Signaling through individual Ras proteins in the absence of the Nf1-RASGAP. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr IA10. doi: 10.1158/1557-3125.RASONC14-IA10