Overcoming amino-Nogo-induced inhibition of cell spreading and neurite outgrowth by 12-O-tetradecanoylphorbol-13-acetate-type tumor promoters.
The N-terminal domain of NogoA, called amino-Nogo, inhibits axonal outgrowth and cell spreading via a largely unknown mechanism. In the present study, we show that amino-Nogo decreases Rac1 activity and inhibits fibroblast spreading. 12-O-Tetradecanoylphorbol-13-acetate-type tumor promoters, such as phorbol 12-myristate 13-acetate (PMA) and teleocidin, increase Rac1 activity and overcome the amino-Nogo-induced inhibition of cell spreading. The stimulating effect of tumor promoters on cell spreading requires activation of protein kinase D and the subsequent activation of Akt1. Furthermore, we identified Akt1 as a new signaling component of the amino-Nogo pathway. Akt1 phosphorylation is decreased by amino-Nogo. Activation of Akt1 with a cell-permeable peptide, TAT-TCL1, blocks the amino-Nogo inhibition. Finally, we provide evidence that these signaling pathways operate in neurons in addition to fibroblasts. Our results suggest that activation of protein kinase D and Akt1 are approaches to promote axonal regeneration after injury.
Deng
Kangwen
K
Neuroscience Research, Pfizer Global Research and Development, Princeton, New Jersey 08543, USA.
Gao
Ying
Y
Cao
Zixuan
Z
Graziani
Edmund I
EI
Wood
Andrew
A
Doherty
Patrick
P
Walsh
Frank S
FS
D016475:3T3 Cells; D000818:Animals; D002273:Carcinogens; D002448:Cell Adhesion / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D006131:Growth Inhibitors; D006801:Humans; D051379:Mice; D009185:Myelin Proteins / Q000494:pharmacology*; D009416:Nerve Regeneration; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism; D000070798:Nogo Proteins; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D002273:Carcinogens; D006131:Growth Inhibitors; D009185:Myelin Proteins; D000070798:Nogo Proteins; C107953:RAC1 protein, human; C000603199:RTN4 protein, human; C000603201:Rtn4 protein, mouse; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; D013755:Tetradecanoylphorbol Acetate