Neurofibromatosis type I (NF1) affects 1 out of 3500 individuals, who have an approximate 10% lifetime riskof developing a NF1 related malignancy. Loss of NF1 provokes a variety of clinical manifestations, some ofwhich are devastating. Life threatening manifestations can arise from the progression to malignant peripheralnerve tumors (MPNSTs). Currently the only treatments are only rarely effective. Molecularly, NF1 results inthe activation of the Ras oncogene and in some cases a rise in cAMP levels. Ras activation results in thestimulation of two signaling pathways which mediate oncogenesis: the class 1 PI3K and RAF kinasesignaling pathways. Activation of the PI3K pathway leads to the inhibition of the Tuberous Sclerosis Complex(TSC) tumor suppressor (TSC1/2) through phosphorylation of TSC2. In turn, activation of the RAF kinasepathway induces the sequential stimulation of two kinases that have been shown to phosphor/late TSC2 atdistinct phosphorylation sites, raising the possibility that the RAF pathway may also mediate inhibition ofTSC1/2 in NF1. Inhibition of TSC1/2 increases the GTP-bound form of Rheb, which stimulates themammalian Target Of Rapamycin (mTOR), a large protein kinase. mTOR mediates the phosphorylation of anumber of downstream substrates implicated in cell growth, such as S6 kinase 1 (S6K1) and initiation factor4E binding protein (4E-BP1). Studies in Drosophila and mice argue that the effects on growth in a TSC1/2deficient setting are largely mediated through S6K1. Moreover the mTOR/S6K1 signaling pathway is alsoregulated by nutrients, and we have recently found that the nutrient pathway is controlled through class 3PI3K (hVps34), which itself is regulated by protein kinase A (PKA). As loss of NF1 function also leads to arise in PKA signaling, our model is that activation of PKA in NF1 mutant cells may drive S6K1 activationindependent of the class 1 PI3K or RAF. Here we have outlined experiments which will allow us to (1)discern the contribution of the PI3K and RAF pathways in NF1, (2) the importance of PKA activation,mediated by hVps34, in NF1, and (3) the role of S6K1 in mediating these neoplastic response in NF1. In thelong term, working with the members of the Cincinnati Center for Neurofibromatosis Research, we proposeto develop targeted therapies against specific cellular proteins known to be deregulated in NF1 pathologies.
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