GEFT, a Rho family guanine nucleotide exchange factor, regulates neurite outgrowth and dendritic spine formation.
The Rho family of small GTPases controls a wide range of cellular processes in eukaryotic cells, such as normal cell growth, proliferation, differentiation, gene regulation, actin cytoskeletal organization, cell fate determination, and neurite outgrowth. The activation of Rho-GTPases requires the exchange of GDP for GTP, a process catalyzed by the Dbl family of guanine nucleotide exchange factors. We demonstrate that a newly identified guanine nucleotide exchange factor, GEFT, is widely expressed in the brain and highly concentrated in the hippocampus, and the Purkinje and granular cells of the cerebellum. Exogenous expression of GEFT promotes dendrite outgrowth in hippocampal neurons, resulting in spines with larger size as compared with control spines. In neuroblastoma cells, GEFT promotes the active GTP-bound state of Rac1, Cdc42, and RhoA and increases neurite outgrowth primarily via Rac1. Furthermore, we demonstrated that PAK1 and PAK5, both downstream effectors of Rac1/Cdc42, are necessary for GEFT-induced neurite outgrowth. AP-1 and NF-kappaB, two transcriptional factors involved in neurite outgrowth and survival, were up-regulated in GEFT-expressing cells. Together, our data suggest that GEFT enhances dendritic spine formation and neurite outgrowth in primary neurons and neuroblastoma cells, respectively, through the activation of Rac/Cdc42-PAK signaling pathways.
Alkek Institute of Biosciences and Technology, and Department of Medical Biochemistry and Genetics, Texas A and M University System Health Science Center, Houston, TX 77030, USA.
Brad
B
Bryan
Vikas
V
Kumar
Lewis Joe
LJ
Stafford
Yi
Y
Cai
Gangyi
G
Wu
Mingyao
M
Liu
D000818:Animals; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D016501:Neurites / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein / Q000502:physiology
C475063:ARHGEF25 protein, human; D020662:Guanine Nucleotide Exchange Factors; D016328:NF-kappa B; D064067:Rho Guanine Nucleotide Exchange Factors; D018808:Transcription Factor AP-1; C443802:PAK5 protein, human; C515903:PAK1 protein, human; C515906:Pak1 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein