| Neurofibromatosis Type 1 (NF1) is a human genetic disorder characterized by various phenotypic features including peripheral nerve sheath tumors primarily made up of Schwann cells. The missing gene in this disease codes for a protein called neurofibromin. Hyperplasia in NF1 Schwann cells has been linked to the absence of the GTPase activating protein (GAP) domain of the neurofibromin protein. However, additional abnormalities may contribute to the formation of NF1 tumors.;Previously, our laboratory has reported that NF1 Schwann cells abnormally express high levels of the tyrosine kinase cell surface receptor c-kit (Badache et al., 1998). A developmental study indicates that c-kit expression is high in the neonatal nerve and declines to its lowest level in the adult. In addition, survival assays revealed that the activation of c-kit by stem cell factor (SCF) in neonatal Schwann cells prevents apoptosis. In the NF1 derived Schwann cells overexpression of c-kit may contribute to the formation of NF1 tumors by preventing apoptosis.;In addition, NF1 Schwann cells also express the PDGF receptor, which belongs to the same receptor class as c-kit. Immunoblot analysis revealed similar levels of PDGF receptor expression in NF1 Schwann cells relative to normal adult human Schwann cells. Although stimulation of the PDGF receptor activates the ERK and PI3K pathways in the normal and NF1 derived Schwann cells, activation of the calcium signaling pathway is only observed in NF1 Schwann cells. The PDGF-receptor linked to the aberrant calcium signaling in NF1 Schwann cells may further contribute to tumor formation.;Furthermore, we found that normal human Schwann cells express 4 isoforms of adenylyl cyclase (AC) and only one isoform of the prostaglandin receptor (EP2) while the NF1 Schwann cells express 7 isoforms of AC and 2 prostaglandin receptors (EP2 and EP4). Therefore, the increased levels of prostaglandin secretion coupled with increased prostaglandin receptor expression and increased AC expression by NFl Schwann cells may lead to the observed elevated levels of intracellular cAMP and contribute to Schwann cell hyperplasia.;In conclusion, these changes in cell surface receptor expression and intracellular signaling in Schwann cells all contribute to the formation of NF1 tumors. |
