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.
Starinsky-Elbaz
Sigal
S
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Faigenbloom
Lior
L
Friedman
Eitan
E
Stein
Reuven
R
Kloog
Yoel
Y
D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D051339:Actin Depolymerizing Factors; D025542:Neurofibromin 1; D011993:Recombinant Fusion Proteins; D054461:Lim Kinases; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein