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Review
. 2021 Jun 25;10(7):1599.
doi: 10.3390/cells10071599.

Fe65: A Scaffolding Protein of Actin Regulators

Vanessa Augustin  1 , Stefan Kins  1
Affiliations
Review

Fe65: A Scaffolding Protein of Actin Regulators

Vanessa Augustin et al. Cells. .

Abstract

The scaffolding protein family Fe65, composed of Fe65, Fe65L1, and Fe65L2, was identified as an interaction partner of the amyloid precursor protein (APP), which plays a key function in Alzheimer's disease. All three Fe65 family members possess three highly conserved interaction domains, forming complexes with diverse binding partners that can be assigned to different cellular functions, such as transactivation of genes in the nucleus, modulation of calcium homeostasis and lipid metabolism, and regulation of the actin cytoskeleton. In this article, we rule out putative new intracellular signaling mechanisms of the APP-interacting protein Fe65 in the regulation of actin cytoskeleton dynamics in the context of various neuronal functions, such as cell migration, neurite outgrowth, and synaptic plasticity.

Keywords: Arf6; Arp2/3; DOCK; ELMO; Mena; Rac; Tip60; cortactin; neurite outgrowth; structural synaptic plasticity.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Putative new role of Fe65 in regulating actin dynamics. Fe65 associates with ELMO1/DOCK1 and Arf6 to form a functional complex that is translocated to the plasma membrane and trapped by APP or other potential receptors, such as the ApoE receptor. Arf6-bound GDP gets replaced with GTP via EFA6/ARNO. Subsequent activation of Rac1 induces a cascade inhibiting the severing activity of cofilin and promoting the polymerization of branched actin, which results in the formation of lamellipodia and the induction of dendritic spine plasticity. The Fe65–Tip60 complex may additionally adjust the association of cortactin to actin by acetylation. In a second potential pathway membrane, receptor-bound Fe65 bind to the polymerization-competent complex of Mena, profilin, and monomeric G-actin that supports the elongation of unbranched actin, leading to filopodia formation and dendritic spine initiation. During migration and outgrowth, it is very likely that these processes are regulated dynamically in a homeostasis. ELMO1, engulfment and cell motility protein 1; EAD, ELMO autoregulatory domain; EID, ELMO inhibitory domain; Arf6, ADP-ribosylation factor 6; GDP, guanosine diphosphate; GTP, guanosine triphosphate; WW, tryptophan-tryptophan domain; PTB1/2, phosphotyrosine binding domain 1/2; DOCK1, dictator of cytokinesis 1; APP, amyloid precursor protein; EFA6, exchange factor for Arf6; ARNO, ADP-ribosylation factor nucleotide-binding site opener; Rac1, ras-related C3 botulinum toxin substrate 1; PAK, p21-activated kinase; LIMK, LIM kinase; Tip60, Tat-interacting protein 60 kDa; N-WASP, neural Wiskott–Aldrich syndrome protein; WAVE, WASP family verprolin homologous protein; Arp2/3, actin related protein 2/3; Mena, mammalian enabled; EVH1/2, Ena/VASP homology domain 1/2; Pro, proline-rich region; G-actin, globular actin.
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