Defining the precise function of specific Ras proteins in mediating normal Schwann cell and NF1 mutant Schwann cell phenotypes
Neurofibromin, the product of the NF1 gene, is one of a family of GTPase activating proteins (GAPs) that accelerate hydrolysis of active Ras-GTP to inactive Ras-GDP. Loss of neurofibromin (through mutations in NF1) causes a failure to terminate Ras signals and increases levels of active Ras. Our lab has previously shown that Schwann cells cultured from human neurofibromas have high levels of active Ras. Additionally, we've shown that an FPTI (a drug that inhibits some Ras processing) obtained from Merck Research Laboratories inhibits growth of NF1 mutant Schwann cells and collegues showed that this was also true for MPNST cells. Not only did these results suggest the possible effeicacy of FPTIs in treatment of NF1 (currently in cincial trials for plexiform neurofibromas in the NF1 Clinic at Children's Hospital), but these results also provide evidence of a key role for Ras signaling in the development of neurofibromas and MPNSTs. There are many different members of the Ras protein family which can affect different cellular responses. Our lab is interested in elucidating the role of Ras proteins in the development of neurofribomas /MPNST.
Using cDNA microarrays, we found that brain lipid binding protein (BLBP) is elevated in an EGFR-positive subpopulation of Nf1 mutant mouse Schwann cells (Nf1/ TXF) that grows away from axons (normal Schwann cell-axon interaction is depicted in A, NF1 mutant TXF cell-axon interaction depicted in C). BLBP-blocking antibodies enabled process outgrowth from Nf1/ TXF cells and restored interaction with axons (D).
Shyra J. Miller, H Li, T Rizvi,Y Huang, GJohansson, J Bowersock A Sidani, J Vitullo, K Vogel, L Parysek, J DeClue, and N Ratner. Brain lipid binding protein in axon-Schwann cell interactions and peripheral nerve tumorigenesis. Mol Cell Biol. 2003 Mar;23(6):2213-24.
