Fe65: A Scaffolding Protein of Actin Regulators

Augustin, Vanessa; Kins, Stefan

doi:10.3390/cells10071599

Cited by 9 publications

(11 citation statements)

References 276 publications

(412 reference statements)

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“…Of note, the level of calcium transporter SERCA2 is increased in FE65/FE65L1 double KO mice which suggest a role of FE65 in calcium homeostasis [ 42 ]. On the other hand, both ARF6 signalling and FE65 have been associated with lipid metabolism through the regulation of lipid-modifying enzymes [ 43 , 44 ] and binding to the low-density lipoprotein receptor family proteins [ 3 ], respectively. As aberrant calcium homeostasis and lipid metabolism have been observed in Alzheimer's disease [ 45 , 46 ] and FE65 is implicated in the pathogenesis of the disease [ 3 ], it is worthwhile to determine the roles of the ARF6-ARNO-FE65-ELMO1-DOCK180 multimeric complex in both physiological and pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

“…FE65, also known as amyloid precursor protein-binding family B member 1, is a 97 kDa brain-enriched adaptor protein with three distinct protein–protein interaction domains: a tryptophan–tryptophan (ww) domain and two successive phosphotyrosine-binding (ptb) domains. Using these domains, FE65 complexes with different interacting partners trigger various biological processes including the regulation of cytoskeleton dynamics [ 3 ]. We previously demonstrated that FE65 interacts with ARF6 via its PTB1 domain and potentiates ARF6-mediated neurite outgrowth [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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ARNO is recruited by the neuronal adaptor FE65 to potentiate ARF6-mediated neurite outgrowth

Zhai

Chan

et al. 2022

Open Biol.

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ADP-ribosylation factor 6 (ARF6) is a small GTPase that has a variety of neuronal functions including stimulating neurite outgrowth, a crucial process for the establishment and maintenance of neural connectivity. As impaired and atrophic neurites are often observed in various brain injuries and neurological diseases, understanding the intrinsic pathways that stimulate neurite outgrowth may provide insights into developing strategies to trigger the reconnection of injured neurons. The neuronal adaptor FE65 has been shown to interact with ARF6 and potentiate ARF6-mediated neurite outgrowth. However, the precise mechanism that FE65 activates ARF6 remains unclear, as FE65 does not possess a guanine nucleotide exchange factor (GEF) domain/function. Here, we show that FE65 interacts with the ARF6 GEF, namely the ARF nucleotide-binding site opener (ARNO). Moreover, a complex consisting of ARNO, ARF6 and FE65 is detected. Notably, FE65 potentiates the stimulatory effect of ARNO on ARF6-mediated neurite outgrowth, and the effect of FE65 is abrogated by an FE65 mutation that disrupts FE65–ARNO interaction. Additionally, the intramolecular interaction for mediating the autoinhibited conformation of ARNO is attenuated by FE65. Moreover, FE65 potentiates the effects of wild-type ARNO, but not the monomeric mutant, suggesting an association between FE65 and ARNO dimerization. Collectively, we demonstrate that FE65 binds to and activates ARNO and, consequently, potentiates ARF6-mediated neurite outgrowth.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ARNO is recruited by the neuronal adaptor FE65 to potentiate ARF6-mediated neurite outgrowth

Zhai

Chan

et al. 2022

Open Biol.

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“…Fe65 † APP, Mena Scaffolding protein that interacts with APP; indirectly induces actin polymerization through Mena (Augustin and Kins, 2021).…”

Section: Name Target Functionmentioning

confidence: 99%

“…Fe65, a scaffold protein family, interacts with and alters the processing of APP ( Augustin and Kins, 2021 ). Fe65 is mainly enriched in the brain, and its overexpression has been shown to reduce Aβ levels in AD model mice ( McLoughlin and Miller, 2008 ).…”

Section: Other Actin-associated Proteins Involved In Cytoskeletal Dys...mentioning

confidence: 99%

Cytoskeletal dysregulation and neurodegenerative disease: Formation, monitoring, and inhibition of cofilin-actin rods

Wurz

Schulz

O’Bryant

et al. 2022

Front. Cell. Neurosci.

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The presence of atypical cytoskeletal dynamics, structures, and associated morphologies is a common theme uniting numerous diseases and developmental disorders. In particular, cytoskeletal dysregulation is a common cellular feature of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. While the numerous activators and inhibitors of dysregulation present complexities for characterizing these elements as byproducts or initiators of the disease state, it is increasingly clear that a better understanding of these anomalies is critical for advancing the state of knowledge and plan of therapeutic attack. In this review, we focus on the hallmarks of cytoskeletal dysregulation that are associated with cofilin-linked actin regulation, with a particular emphasis on the formation, monitoring, and inhibition of cofilin-actin rods. We also review actin-associated proteins other than cofilin with links to cytoskeleton-associated neurodegenerative processes, recognizing that cofilin-actin rods comprise one strand of a vast web of interactions that occur as a result of cytoskeletal dysregulation. Our aim is to present a current perspective on cytoskeletal dysregulation, connecting recent developments in our understanding with emerging strategies for biosensing and biomimicry that will help shape future directions of the field.

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“…The crosstalk between LDL receptors and APP is even more complex if we look at another interactor known as FE65, a cytoplasmic adaptor protein [ 86 ]. In fact, LRP1, LRP8 and VLDLR bind to FE65, forming different tripartite complexes, which may modulate APP endocytic trafficking, Aβ production, APP intracellular domain (AICD) nuclear trafficking and DNA protection [ 85 , 87 ]. Notably, AICD, along with FE65 and Tip60/Kat5, a lysine acetyltransferase regulating hippocampal gene network linked to memory formation [ 88 ], associates into complexes in nuclear transcription factories, while the C-terminal portions of LDL receptors are recruited at a nuclear level upon gamma-secretase cleavage [ 67 , 89 ].…”

Section: Ldl Receptor Interactors In Normal and Pathological Brain Co...mentioning

confidence: 99%

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

Passarella

Ronci

Liberto

et al. 2022

IJMS

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Recent studies have highlighted the mechanisms controlling the formation of cerebral cholesterol, which is synthesized in situ primarily by astrocytes, where it is loaded onto apolipoproteins and delivered to neurons and oligodendrocytes through interactions with specific lipoprotein receptors. The “cholesterol shuttle” is influenced by numerous proteins or carbohydrates, which mainly modulate the lipoprotein receptor activity, function and signaling. These molecules, provided with enzymatic/proteolytic activity leading to the formation of peptide fragments of different sizes and specific sequences, could be also responsible for machinery malfunctions, which are associated with neurological, neurodegenerative and neurodevelopmental disorders. In this context, we have pointed out that purines, ancestral molecules acting as signal molecules and neuromodulators at the central nervous system, can influence the homeostatic machinery of the cerebral cholesterol turnover and vice versa. Evidence gathered so far indicates that purine receptors, mainly the subtypes P2Y2, P2X7 and A2A, are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Niemann–Pick C diseases, by controlling the brain cholesterol homeostasis; in addition, alterations in cholesterol turnover can hinder the purine receptor function. Although the precise mechanisms of these interactions are currently poorly understood, the results here collected on cholesterol–purine reciprocal control could hopefully promote further research.

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Fe65: A Scaffolding Protein of Actin Regulators

Cited by 9 publications

References 276 publications

ARNO is recruited by the neuronal adaptor FE65 to potentiate ARF6-mediated neurite outgrowth

ARNO is recruited by the neuronal adaptor FE65 to potentiate ARF6-mediated neurite outgrowth

Cytoskeletal dysregulation and neurodegenerative disease: Formation, monitoring, and inhibition of cofilin-actin rods

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

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