FE65 interacts with ADP-ribosylation factor 6 to promote neurite outgrowth
Open accessAbstract
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.—Cheung, H. N., Dunbar, C., Mórotz, G. M., Cheng, W. H., Chan, H. Y., Miller, C. C., Lau, K.‐.F. FE65 interacts with ADP‐ribosylation factor 6 to promote neurite outgrowth. FASEB J . 28, 337–349 (2014). www.fasebj.org
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Apbb1 is an adapter protein that functions in neurite outgrowth and synaptic plasticity, processes linked to neurological disorders including ASD.
“Apbb1 is an adapter protein that functions in neurite outgrowth (Cheung et al., 2014; Ikin et al., 2007) and synaptic plasticity (Sabo et al., 2003), processes that have been linked to neurological disorders including ASD (Hussman et al., 2011)”
From A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains (2014) · cites this paper as Cheung et al., 2014
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A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains
Irimia, M., Weatheritt, R. J., Ellis, J. D., Parikshak, N. N., Gonatopoulos-Pournatzis, T., Babor, M., Quesnel-Vallières, M., Tapial, J., Raj, B., O’Hanlon, D., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.035 · Cited by 693 · see citing works
“Apbb1 is an adaptor protein that functions in neurite outgrowth (Cheung et al., 2014; Ikin et al., 2007) and synaptic plasticity (Sabo et al.”
BackgroundNot just amyloid: physiological functions of the amyloid precursor protein family
Müller, U. C., Deller, T., & Korte, M. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.29 · Cited by 634 · see citing works
Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development
Quesnel-Vallières, M., Irimia, M., Cordes, S. P., & Blencowe, B. J. (2015) · Genes & Development · doi:10.1101/gad.256115.114 · Cited by 155 · see citing works
Bukhari, H., Glotzbach, A., Kolbe, K., Leonhardt, G., Looße, C., & Müller, T. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.05.005 · Cited by 88 · see citing works
Santana, J., & Marzolo, M. (2017) · Biochemical Journal · doi:10.1042/bcj20160628 · Cited by 74 · see citing works
Rab‐mediated trafficking role in neurite formation
Villarroel‐Campos, D., Gastaldi, L., Conde, C. B., Cáceres, A., & González-Billault, C. E. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12676 · Cited by 69 · see citing works
Ohnishi, T., Shirane, M., & Nakayama, K. I. (2017) · Scientific Reports · doi:10.1038/srep41130 · Cited by 47 · see citing works
Tang, W., Tam, J. H. K., Seah, C., Chiu, J., Tyrer, A. E., Cregan, S. P., Meakin, S. O., & Pasternak, S. (2015) · Molecular Brain · doi:10.1186/s13041-015-0129-7 · Cited by 42 · see citing works
Pérez-González, M., Mendióroz, M., Badesso, S., Sucunza, D., Roldán, M., Espelosin, M., Ursúa, S., Luján, R., Cuadrado‐Tejedor, M., & García‐Osta, A. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101818 · Cited by 42 · see citing works
APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins
Guénette, S. Y., Strecker, P., & Kins, S. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00087 · Cited by 39 · see citing works
Genetically Encoded Calcium Indicators Can Impair Dendrite Growth of Cortical Neurons
Köhler, I., Jäck, A., Stahlhut, T., Rennau, L.-M., Gonda, S., & Wahle, P. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.570596 · Cited by 32 · see citing works
Amyloid precursor protein and its interacting proteins in neurodevelopment
Chau, D. D., Ng, L. L.-H., Zhai, Y., & Lau, K. (2023) · Biochemical Society Transactions · doi:10.1042/bst20221527 · Cited by 31 · see citing works
Self-citationRegulation of neuronal survival and morphology by the E3 ubiquitin ligase RNF157
Matz, A., Lee, S., Schwedhelm‐Domeyer, N., Zanini, D., Holubowska, A., Kannan, M., Farnworth, M. S., Jahn, O., Göpfert, M. C., & Stegmüller, J. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.163 · Cited by 31 · see citing works
Schöler, J., Ferralli, J., Thiry, S., & Chiquet‐Ehrismann, R. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.615922 · Cited by 29 · see citing works
Neuronal adaptor FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1
Li, W., Tam, K. M. V., Chan, W. W. R., Koon, A. C., Ngo, J. C. K., Chan, H. Y. E., & Lau, K. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000505 · Cited by 28 · see citing works
Self-citationStrecker, P., Ludewig, S., Rust, M. B., Mundinger, T. A., Görlich, A., Krächan, E. G., Mehrfeld, C., Herz, J., Körte, M., Guénette, S. Y., et al. (2016) · Scientific Reports · doi:10.1038/srep25652 · Cited by 23 · see citing works
Chan, W. W. R., Li, W., Chang, R. C. C., & Lau, K. (2020) · The FASEB Journal · doi:10.1096/fj.202001703r · Cited by 20 · see citing works
Self-citationPhosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing
Lee, Y. S., Chow, W. N. V., & Lau, K. (2017) · Scientific Reports · doi:10.1038/s41598-017-12334-2 · Cited by 18 · see citing works
Self-citationRegulation of Neurotransmitter Release by Amyloid Precursor Protein Through Synapsin Phosphorylation
Liu, A., Zhang, Y., Han, L., He, G., Xie, W., Zhou, Z., & Jia, Z. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2418-2 · Cited by 18 · see citing works
Fe65: A Scaffolding Protein of Actin Regulators
Augustin, V., & Kins, S. (2021) · Cells · doi:10.3390/cells10071599 · Cited by 18 · see citing works
FE65: Roles beyond amyloid precursor protein processing
Chow, W. N. V., Cheung, H. N. M., Li, W., & Lau, K. (2015) · Cellular & Molecular Biology Letters · doi:10.1515/cmble-2015-0002 · Cited by 16 · see citing works
Self-citationDing, Z., Ren, J., Tan, J.-M., Wang, Z., Yin, S., Huang, Y. K., Huang, X., Wang, W., Lan, J.-F., & Ren, Q. (2014) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2014.10.006 · Cited by 15 · see citing works
Zhang, Y. C., Li, Z., Guan, H., Qiu, Z., & Zou, C. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70548 · Cited by 15 · see citing works
Chen, F., Zhang, W., Xu, S., Zhang, H., Chen, L., Chen, C., Zhu, Z., & Zhao, Y. (2023) · Journal of Ginseng Research · doi:10.1016/j.jgr.2023.04.007 · Cited by 10 · see citing works
Physiological and Pathological Roles of the Cytohesin Family in Neurons
Ito, A., Fukaya, M., Okamoto, H., & Sakagami, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095087 · Cited by 9 · see citing works
GULP1/CED-6 ameliorates amyloid-β toxicity in a Drosophila model of Alzheimer’s disease
Chiu, W. Y. V., Koon, A. C., Ngo, J. C. K., Chan, H. Y. E., & Lau, K. (2017) · Oncotarget · doi:10.18632/oncotarget.20062 · Cited by 9 · see citing works
Self-citationChau, D. D., Li, W., Chan, W. W. R., Sun, J. K., Zhai, Y., Chow, H., & Lau, K. (2022) · The FASEB Journal · doi:10.1096/fj.202200757r · Cited by 8 · see citing works
Self-citationSuh, J., Moncaster, J. A., Wang, L., Hafeez, I., Herz, J., Tanzi, R. E., Goldstein, L. E., & Guénette, S. Y. (2015) · The FASEB Journal · doi:10.1096/fj.14-261453 · Cited by 8 · see citing works
ARNO is recruited by the neuronal adaptor FE65 to potentiate ARF6-mediated neurite outgrowth
Zhai, Y., Chan, W. W. R., Li, W., & Lau, K. (2022) · Open Biology · doi:10.1098/rsob.220071 · Cited by 7 · see citing works
Self-citationSmall GTPases control macropinocytosis of amyloid precursor protein and cleavage to amyloid-β
Chiu, J., Krupa, J. M., Seah, C., & Pasternak, S. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e31077 · Cited by 4 · see citing works
Emerging roles of the neural adaptor FE65 in neurite outgrowth
Li, W., Chan, W. W. R., Ngo, J. C. K., & Lau, K.-F. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.241449 · Cited by 4 · see citing works
Self-citationBlockus, H., & Chédotal, A. (2015) · Wiley eBooks · doi:10.1002/9781118524947.ch8 · Cited by 2 · see citing works
An Enhanced Green Fluorescence Protein-based Assay for Studying Neurite Outgrowth in Primary Neurons
Chan, W. W. R., Li, W., Chau, D. L. D., & Lau, K. (2019) · Journal of Visualized Experiments · doi:10.3791/60031 · Cited by 1 · see citing works
Self-citationThe Rho GTPases Rac1, Cdc42, and RhoA Regulate APP Transport to Lysosomes and Aβ Production
Chiu, & Justin, K. (2015) · Scholarship@Western (Western University)
Wang, L., Li, H., Zhou, Y., Qin, Y., Wang, Y., Liu, B., & Qian, H. (2016) · Canadian Journal of Microbiology · doi:10.1139/cjm-2015-0550
Takahashi, M., Yako, H., Miyamoto, Y., Kukimoto‐Niino, M., Shirouzu, M., & Yamauchi, J. (2026) · Scientific Reports · doi:10.1038/s41598-026-39722-x
Physiological and pathological roles of the amyloid precursor protein at the presynapse
Jordá-Siquier, T. (2021) · theses.fr (ABES) · doi:10.70675/3bff9a77z3935z4d28zb02bz5b454bcbc77e
- Authors
- Cheung, H. N. M., Dunbar, C., Mórotz, G. M., Cheng, W. H., Chan, H. Y. E., Miller, C. C. J., & Lau, K.
- Affiliations
- Chinese University of Hong Kong (HK)
- King's College London (GB)
- Corresponding author
- Lau, Kwok‐Fai
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2013-09-20
- Volume
- 28
- Issue
- 1
- Pages
- 337-349
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC4516155
- OpenAlex
- W2034868654
- Cited by
- 37
- References
- 93
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 8 · 2016: 2 · 2015: 7 · 2014: 4
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Fe65, ARF6, neurite outgrowth, Rac1, phosphotyrosine binding domain, small GTPase activation, growth cones, amyloid precursor protein, Alzheimer's disease, actin dynamics, neuronal development
- MeSH terms
- ADP-Ribosylation Factor 6, Animals, Cells, Cultured, Cricetulus, Nerve Tissue Proteins, Nuclear Proteins, Protein Binding, CHO Cells, Neurites, ADP-Ribosylation Factors, Two-Hybrid System Techniques, Immunoprecipitation, Rats
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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