Cellular and subcellular localization of EFA6C, a third member of the EFA6 family, in adult mouse Purkinje cells

Matsuya, Shigetsune; Sakagami, Hiroyuki; Tohgo, Akira; Owada, Yuji; Shin, Hye Won; Takeshima, Hiroshi; Nakayama, Kazuhisa; Kokubun, S.; Kondo, Hisatake

doi:10.1111/j.1471-4159.2005.03421.x

Cited by 3 publications

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“…EFA6C is expressed exclusively in the cerebellar Purkinje cells (Matsuya et al . ), whereas EFA6D is widely expressed throughout the brain (Sakagami et al . ).…”

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EFA6A, a guanine nucleotide exchange factor for Arf6, interacts with sorting nexin‐1 and regulates neurite outgrowth

Fukaya

Fukushima

Hara

et al. 2013

Journal of Neurochemistry

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The membrane trafficking and actin cytoskeleton remodeling mediated by ADP ribosylation factor 6 (Arf6) are functionally linked to various neuronal processes including neurite formation and maintenance, neurotransmitter release, and receptor internalization. EFA6A is an Arf6-specific guanine nucleotide exchange factor that is abundantly expressed in the brain. In this study, we identified sorting nexin-1 (SNX1), a retromer component that is implicated in endosomal sorting and trafficking, as a novel interacting partner for EFA6A by yeast two-hybrid screening. The interaction was mediated by the Cterminal region of EFA6A and a BAR domain of SNX1, and further confirmed by pull-down assay and immunoprecipitation from mouse brain lysates. In situ hybridization analysis demonstrated the widespread expression of SNX1 in the mouse brain, which overlapped with the expression of EFA6A in the forebrain. Immunofluorescent analysis revealed the partial colocalization of EFA6A and SNX1 in the dendritic fields of the hippocampus. Immunoelectron microscopic analysis revealed the overlapping subcellular localization of EFA6A and SNX1 at the post-synaptic density and endosomes in dendritic spines. In Neuro-2a neuroblastoma cells, expression of either EFA6A or SNX1 induced neurite outgrowth, which was further enhanced by co-expression of EFA6A and SNX1. The present findings suggest a novel mechanism by which EFA6A regulates Arf6-mediated neurite formation through the interaction with SNX1. Keywords: ADP ribosylation factor, dendritic spine, guanine nucleotide exchange factor, membrane traffic, post-synaptic density. The endocytic system comprises various membrane compartments including early endosomes, recycling endosomes, late endosomes, lysosomes, and the trans-Golgi network (Maxfield and McGraw 2004). The endosomal trafficking of membrane components at appropriate places and timing is intimately linked to a variety of neuronal functions including neuronal polarity, migration, neurite formation, synaptic connection, neurotransmitter release, and receptor surface expression (Kennedy and Ehlers 2006;Schmidt and Haucke 2007;Kawauchi 2012;Yap and Winckler 2012). During neurite formation, the polarized delivery of membrane components to growing neurite tips through the endocytic system is required for vectorial neurite outgrowth and extension (Tang 2008;Sann et al. 2009). Once synaptic connections are established, activity-dependent changes in synaptic efficiency and structures are regulated by endosomal trafficking of membrane components such as a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptors (AMPARs) from dendritic recycling endosomes to the post-synaptic spine membrane, which underlies a fundamental mechanism for synaptic plasticity (Hanley 2010; Anggono and Huganir 2012). Various small GTPases, particularly the ADP ribosylation factor (Arf) and Rab families, have been recognized as critical regulators of Received September 5, 2013; revised manuscript received October 9, 2013; accepted November 4...

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“…EFA6C is expressed exclusively in the cerebellar Purkinje cells (Matsuya et al . ), whereas EFA6D is widely expressed throughout the brain (Sakagami et al . ).…”

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confidence: 99%

EFA6A, a guanine nucleotide exchange factor for Arf6, interacts with sorting nexin‐1 and regulates neurite outgrowth

Fukaya

Fukushima

Hara

et al. 2013

Journal of Neurochemistry

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“…EFA6, the prototypical representative of the third group of ARF–GEFs, is more similar to the cytohesins but contains several coiled‐coil‐like and proline‐rich elements (19). The EFA6 subfamily consists of four members, EFA6a–d (19–23). In vitro , most ARF–GEFs are relatively promiscuous with respect to their exchange activity toward different ARF‐GTPases, with the exception of EFA6, which is a specific exchange factor for ARF6 (19).…”

Section: The Cytohesin Family Of Arf–gefsmentioning

confidence: 99%

Guanine nucleotide exchange factors of the cytohesin family and their roles in signal transduction

Kolanus

2007

Immunological Reviews

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Members of the cytohesin protein family, a group of guanine nucleotide exchange factors for adenosine diphosphate ribosylation factor (ARF) guanosine triphosphatases, have recently emerged as important regulators of signal transduction in vertebrate and invertebrate biology. These proteins share a modular domain structure, comprising carboxy-terminal membrane recruitment elements, a Sec7 homology effector domain, and an amino-terminal coiled-coil domain that serve as a platform for their integration into larger signaling complexes. Although these proteins have a highly similar overall build, their individual biological functions appear to be at least partly specific. Cytohesin-1 had been identified as a regulator of beta2 integrin inside-out regulation in immune cells and was subsequently shown to be involved in mitogen-associated protein kinase signaling in tumor cell proliferation as well as in T-helper cell activation and differentiation. Cytohesin-3, which had been discovered to be strongly associated with T-cell anergy, was very recently described as an essential component of insulin signal transduction in Drosophila and in human and murine liver cells. Future work will aim to dissect the mechanistic details of the modes of action of the cytohesins as well as to define the precise roles of these versatile proteins in vertebrates at the genetic level.

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“…In neurons, accumulating evidence indicates that Arf6 regulates a diverse array of neuronal processes related to neuronal morphogenesis and synaptic plasticity including: neuronal migration (Falace et al, ); the formation of axons (Hernandez‐Deviez et al, ), dendrites (Hernandez‐Deviez et al, ), and dendritic spines (Miyazaki et al, ; Choi et al, ; Raemaekers et al, ; Kim et al, ); axonal transport (Eva et al, ); the release and recycling of synaptic vesicles (Galas et al, ; Krauss et al, ); and the trafficking and synaptic expression of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) receptors during hippocampal long‐term potentiation and depression (Scholz et al, ; Oku and Huganir, ; Zheng et al, ). Similar to other small GTPase pathways, in which regulatory proteins outnumber their target small GTPases (Bos et al, ), to date, multiple GEFs and GAPs for Arf6 have been identified, including cytohesin1–3 (Frank et al, ; Langille et al, ; El Azreq et al, ), guanine nucleotide exchange factor for Arf6 (EFA6A–D) (Franco et al, ; Derrien et al, ; Matsuya et al, ; Sakagami et al, ), and BRAG1–3 (Someya et al, ; Sakagami et al, ; Fukaya et al, ) as Arf6‐GEFs, and GIT1–2 (Vitale et al, ), SMAP1‐2 (Tanabe et al, ; Natsume et al, ), ACAP1–2 (Jackson et al, ), ADAP1 (Venkateswarlu et al, ), ARAP2 (Yoon et al, ), ARAP3 (Krugmann et al, ), and AGAP3 (Oku and Huganir, ) as Arf6‐GAPs. The existence of multiple GEFs and GAPs for Arf6 suggests that the spatiotemporal precision of Arf6 activation depends on these regulatory proteins.…”

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“…Of these, three EFA6 members (EFA6A, C, and D) are abundantly expressed in the brain. At the mRNA level, EFA6A is preferentially expressed in the forebrain and cerebellar granule cells (Suzuki et al, ; Sakagami et al, ), whereas EFA6C is restricted to cerebellar Purkinje cells (Matsuya et al, ). At the protein level, EFA6A and EFA6C have a somatodendritic localization (Matsuya et al, ; Sakagami et al, ).…”

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confidence: 99%

“…At the mRNA level, EFA6A is preferentially expressed in the forebrain and cerebellar granule cells (Suzuki et al, ; Sakagami et al, ), whereas EFA6C is restricted to cerebellar Purkinje cells (Matsuya et al, ). At the protein level, EFA6A and EFA6C have a somatodendritic localization (Matsuya et al, ; Sakagami et al, ). Our recent quantitative immunoelectron microscopic analyses showed that EFA6A was preferentially localized at the postsynaptic components such as the postsynaptic density, the plasma membrane, and endosomes in the dendritic spine (Fukaya et al, ).…”

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Distinct subcellular localization of alternative splicing variants of EFA6D, a guanine nucleotide exchange factor for Arf6, in the mouse brain

Fukaya

Ohta

Hara

et al. 2016

J of Comparative Neurology

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EFA6D (guanine nucleotide exchange factor for ADP-ribosylation factor 6 [Arf6]D) is also known as EFA6R, Psd3, and HCA67. It is the fourth member of the EFA6 family with guanine nucleotide exchange activity for Arf6, a small guanosine triphosphatase (GTPase) that regulates endosomal trafficking and actin cytoskeleton remodeling. We propose a classification and nomenclature of 10 EFA6D variants deposited in the GenBank database as EFA6D1a, 1b, 1c, 1d, 1s, 2a, 2b, 2c, 2d, and 2s based on the combination of N-terminal and C-terminal insertions. Polymerase chain reaction analysis showed the expression of all EFA6D variants except for variants a and d in the adult mouse brain. Immunoblotting analysis with novel variant-specific antibodies showed the endogenous expression of EFA6D1b, EFA6D1c, and EFA6D1s at the protein level, with the highest expression being EFA6D1s, in the brain. Immunoblotting analysis of forebrain subcellular fractions showed the distinct subcellular distribution of EFA6D1b/c and EFA6D1s. The immunohistochemical analysis revealed distinct but overlapping immunoreactive patterns between EFA6D1b/c and EFA6D1s in the mouse brain. In immunoelectron microscopic analyses of the hippocampal CA3 region, EFA6D1b/c was present predominantly in the mossy fiber axons of dentate granule cells, whereas EFA6D1s was present abundantly in the cell bodies, dendritic shafts, and spines of hippocampal pyramidal cells. These results provide the first anatomical evidence suggesting the functional diversity of EFA6D variants, particularly EFA6D1b/c and EFA6D1s, in neurons. J. Comp. Neurol. 524:2531-2552, 2016. © 2016 Wiley Periodicals, Inc.

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Cellular and subcellular localization of EFA6C, a third member of the EFA6 family, in adult mouse Purkinje cells

Cited by 3 publications

References 1 publication

EFA6A, a guanine nucleotide exchange factor for Arf6, interacts with sorting nexin‐1 and regulates neurite outgrowth

EFA6A, a guanine nucleotide exchange factor for Arf6, interacts with sorting nexin‐1 and regulates neurite outgrowth

Guanine nucleotide exchange factors of the cytohesin family and their roles in signal transduction

Distinct subcellular localization of alternative splicing variants of EFA6D, a guanine nucleotide exchange factor for Arf6, in the mouse brain

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