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 NF1(1-1163) 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 NF1(1-1163), 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.