Neurofibromatosis type I (NF1) is multisystemic disease characterized by pigmentary skin changes, increased susceptibility to
tumor formation, neurological deficits and skeletal defects. The disease is a monogenic, autosomal dominant disorder, caused by the presence of mutations in the NF1 gene encoding
neurofibromin - a multifunctional regulatory
protein. The basic function of
neurofibromin protein is modulation of the
RAS protein activity necessary for regulation of cell proliferation and differentiation by the RAS/MAPK and RAS/PI3K/AKT signal transduction pathways. In addition,
neurofibromin is a regulator of
adenylate cyclase activity and therefore may interfere with signaling by the
cAMP/protein kinase A pathway that regulates cell cycle progression or learning and memory formation processes.
Neurofibromin also interacts with many other
proteins that are engaged in intracellular transport (
tubulin,
kinesin), actin cytoskeleton rearrangements (LIMK2, Rho and Rac) or morphogenesis of neural cells (
syndecans, CRMP
proteins). The activity of
neurofibromin is strictly regulated by the expression of different NF1
mRNA isoforms depending on tissue type or period in organism development, the
protein localization, posttranslational modifications (phosphorylation, ubiquitination) or interactions with other
proteins (e.g. 14-3-3). The fact that
neurofibromin is engaged in many cellular processes has significant consequences when the proper
protein functioning is impaired due to decreased
protein level or activity. It affects the normal cell function and results in disturbances of organism development that lead to the occurrence of clinical signs specific for NF1. In the article, the basic
neurofibromin functions are presented in the context of the molecular pathogenesis of NF1.