FE65 interacts with ADP-ribosylation factor 6 to promote neurite outgrowth.
FE65 is an adaptor protein that binds to the amyloid precursor protein (APP). As such, FE65 has been implicated in the pathogenesis of Alzheimer's disease. In addition, evidence suggests that FE65 is involved in brain development. It is generally believed that FE65 participates in these processes by recruiting various interacting partners to form functional complexes. Here, we show that via its first phosphotyrosine binding (PTB) domain, FE65 binds to the small GTPase ADP-ribosylation factor 6 (ARF6). FE65 preferentially binds to ARF6-GDP, and they colocalize in neuronal growth cones. Interestingly, FE65 stimulates the activation of both ARF6 and its downstream GTPase Rac1, a regulator of actin dynamics, and functions in growth cones to stimulate neurite outgrowth. We show that transfection of FE65 and/or ARF6 promotes whereas small interfering RNA knockdown of FE65 or ARF6 inhibits neurite outgrowth in cultured neurons as compared to the mock-transfected control cells. Moreover, knockdown of ARF6 attenuates FE65 stimulation of neurite outgrowth and defective neurite outgrowth seen in FE65-deficient neurons is partially corrected by ARF6 overexpression. Notably, the stimulatory effect of FE65 and ARF6 on neurite outgrowth is abrogated either by dominant-negative Rac1 or knockdown of Rac1. Thus, we identify FE65 as a novel regulator of neurite outgrowth via controlling ARF6-Rac1 signaling.
1School of Life Sciences, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China. kflau@cuhk.edu.hk.
Hei Nga Maggie
HN
Cheung
Charlotte
C
Dunbar
Gábor M
GM
Mórotz
Wai Hang
WH
Cheng
Ho Yin Edwin
HY
Chan
Christopher C J
CC
Miller
Kwok-Fai
KF
Lau
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D047468:Immunoprecipitation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D020798:Two-Hybrid System Techniques
D000089982:ADP-Ribosylation Factor 6; C486242:Apbb1 protein, rat; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020727:ADP-Ribosylation Factors; C000715349:Arf6 protein, rat
A4 precursor protein-binding family B member 1; ARF6; Rac1; amyloid-β; neurons