The pre-GAP-related domain of neurofibromin regulates cell migration through the LIM kinase/cofilin pathway

Neurofibromin contains several domains, most notably a GAP-related domain (GRD), that down-regulates Ras pathways. The functions of the non-GRD neurofibromin domains are largely known. Here we show that the pre-GRD region of neurofibromin alters the expression of genes involved in cell adhesion and migration and acts as a negative regulator of the Rac1/Pak1/LIMK1/cofilin pathway. Thus, neurofibromin-deficient glioblastoma and mouse fibroblasts are enriched in Rac1-GTP, p-Pak1, p-LIMK1 and p-cofilin, with all proteins exhibiting decreased expression upon expression of NF11–1163 polypeptide. Concomitantly, actin stress fibers and focal adhesion were disassembled and cell migration was halted. These effects were independent of the Ras signaling pathways. It seems that NF11–1163, through negative regulation of Rac-1, shifts the balance from a state of inactive phospho-cofilin to active unphosphorylated cofilin, resulting in severing of F-actin. Impairment of these cellular functions of neurofibromin provides novel insights into the invasiveness/progression of NF1-associated tumors.