TY - JOUR
T1 - The pre-GAP-related domain of neurofibromin regulates cell migration through the LIM kinase/cofilin pathway
AU - Starinsky-Elbaz, Sigal
AU - Faigenbloom, Lior
AU - Friedman, Eitan
AU - Stein, Reuven
AU - Kloog, Yoel
N1 - Funding Information:
This work was supported by the Israel Science Foundation (ISF), the Chief Scientist Office Israel Ministry of Health, the Gilbert Israeli Neurofibromatosis Center and by the Gilbert Washington Children's National Medical Center.
Funding Information:
This work was supported in by the Israel Science Foundation ( 643/02 to RS) and by the Prajs-Drimmer Institute for the Development of Anti-Degenerative Disease Drugs. We thank S. R. Smith for editorial assistance. Yoel Kloog is the incumbent of The Jack H. Skirball Chair for Applied Neurobiology.
PY - 2009/11
Y1 - 2009/11
N2 - 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.
AB - 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.
KW - GAP-related domain
KW - LIM kinase/cofilin pathway
KW - Neurofibromatosis type 1
KW - Neurofibromin
KW - Pre-GRD function
UR - http://www.scopus.com/inward/record.url?scp=70350749407&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2009.07.014
DO - 10.1016/j.mcn.2009.07.014
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AN - SCOPUS:70350749407
SN - 1044-7431
VL - 42
SP - 278
EP - 287
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
IS - 4
ER -
