The death receptor antagonist FAIM promotes neurite outgrowth by a mechanism that depends on ERK and NF-kapp B signaling.
Fas apoptosis inhibitory molecule (FAIM) is a protein identified as an antagonist of Fas-induced cell death. We show that FAIM overexpression fails to rescue neurons from trophic factor deprivation, but exerts a marked neurite growth-promoting action in different neuronal systems. Whereas FAIM overexpression greatly enhanced neurite outgrowth from PC12 cells and sympathetic neurons grown with nerve growth factor (NGF), reduction of endogenous FAIM levels by RNAi decreased neurite outgrowth in these cells. FAIM overexpression promoted NF-kappa B activation, and blocking this activation by using a super-repressor I kappa B alpha or by carrying out experiments using cortical neurons from mice that lack the p65 NF-kappa B subunit prevented FAIM-induced neurite outgrowth. The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras-ERK pathway. Finally, we show that FAIM interacts with both Trk and p75 neurotrophin receptor NGF receptors in a ligand-dependent manner. These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras-ERK pathway and NF-kappa B.
Sole
Carme
C
Group Cell Signalling and Apoptosis, Department of Basic Medical Sciences, Universitat de Lleida, 25008 Lleida, Spain.
Dolcet
Xavier
X
Segura
Miguel F
MF
Gutierrez
Humberto
H
Diaz-Meco
Maria-Teresa
MT
Gozzelino
Raffaella
R
Sanchis
Daniel
D
Bayascas
Jose R
JR
Gallego
Carme
C
Moscat
Jorge
J
Davies
Alun M
AM
Comella
Joan X
JX
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D015513:Oncogene Proteins / Q000378:metabolism; D016716:PC12 Cells; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; C421307:FAIM protein, human; C498892:Faim protein, mouse; D016328:NF-kappa B; D015513:Oncogene Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; C065400:oncogene protein trk