Coordinated Nuclear and Synaptic Shuttling of Afadin Promotes Spine Plasticity and Histone Modifications

VanLeeuwen, Jon-Eric; Rafalovich, Igor; Sellers, Katherine J.; Jones, Kelly A.; Griffith, Theanne N.; Huda, Rafiq; Miller, Richard J.; Srivastava, Deepak P.; Penzes, Peter

doi:10.1074/jbc.m113.536391

Cited by 23 publications

(38 citation statements)

References 31 publications

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“…Intriguingly, we found that AF6 represses Snail expression depending on AF6's nuclear localization in PC cells. A similar phenomenon of AF6 nuclear localization also was observed when cells were exposed to growth factor signalling, and nuclear localization of AF6 may facilitate the induction of a transcriptional programme 14,[24][25][26] . However, there exists little evidence to show that AF6 can play a role as a transcriptional co-factor.…”

Section: Discussionsupporting

confidence: 52%

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Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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Section: Discussionsupporting

confidence: 52%

“…Accumulating evidence suggests that AF6 is a dual-residency protein, and its nuclear localization and transcriptional repressor activity are closely correlated 14,[24][25][26] . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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“…Previous studies have demonstrated that afadin is a dual residency protein present in both nuclear and cytosolic compartments, and specifically at synapses (Buchert et al, 2007;VanLeeuwen et al, 2014). Moreover, we have recently shown than activity-dependent signaling causes bi-directional trafficking of afadin to discrete nuclear and synaptic sites within the same cell (VanLeeuwen et al, 2014). As acute exposure to estradiol has been shown to also cause the enrichment of afadin at synapses , we reasoned that this may also cause afadin to traffic to the nucleus within the same cell.…”

Section: Acute Estradiol Treatment Causes Bi-directional Trafficking mentioning

confidence: 99%

“…The rapid post-translational modification of H3 has been observed in response to synaptic activity as well as neuromodulators (Brami-Cherrier et al, 2007;Stipanovich et al, 2008;Wittmann et al, 2009;VanLeeuwen et al, 2014). In particular, modulation of H3S10p by these stimuli, is thought to link extracellular signals with chromatin remodeling, and thus the regulation of genes associated with learning and memory (Riccio, 2010;Maze et al, 2013;Watson and Tsai, 2017).…”

Section: Estradiol Rapidly Incudes Phosphorylation Of Histone H3mentioning

confidence: 99%

“…Interestingly, estradiol has been shown to cause acetylation of Histone H3 within 5 minutes in hippocampal neurons, which was necessary for estrogen-dependent consolidation of memory (Zhao et al, 2010;Zhao et al, 2012). Another modification important for memory and that can be induced in response to multiple extracellular stimuli is the phosphorylation of histone H3 protein at serine 10 on its N-terminal tail (Brami-Cherrier et al, 2007;Lubin and Sweatt, 2007;Wittmann et al, 2009;VanLeeuwen et al, 2014). Although such modifications are thought to be important for the encoding of long-lasting memories, the synaptic and cytoplasmic signalling cascades that connect local signalling at synapses with these nucleosomal events are not fully understood (Fainzilber et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Cyto-nuclear shuttling of afadin is required for rapid estradiol-mediated modifications of histone H3

Sellers

Watson

Srivastava

2018

Preprint

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Estrogens have been shown to rapidly regulate local signalling events at both synapses and within the nucleus. The result of these signalling events is to rapidly modulate synapse structure and function, as well as epigenetic mechanisms including histone modifications.Ultimately these mechanisms are thought to contribute to long-lasting changes in neural circuitry, and thus influences cognitive functions such as learning and memory. However, the mechanisms by which estrogen-mediated local synaptic and nuclear signalling events are coordinated are not well understood. In this study we have found that the scaffold protein afadin, (also known as AF-6), undergoes a bi-directional trafficking to both synaptic and nuclear compartment in response to acute 17β-estradiol (estradiol) treatment. Interestingly, nuclear accumulation of afadin was coincidental with an increase in the phosphorylation of histone H3 at serine 10 (H3S10p). This histone modification is associated with the remodelling of chromatin into an open euchromatin state, allowing for transcriptional activation and related learning and memory processes. Critically, the cyto-nuclear trafficking of afadin was required for estradiol-dependent H3S10p. We further determined that nuclear accumulation of afadin is sufficient to induce phosphorylation of the mitogentic kinases ERK1/2 (pERK1/2) within the nucleus. Moreover, nuclear pERK1/2 was required for estradiol-dependent H3S10p. Taken together, we propose a model whereby estradiol incudes the bi-directional trafficking of afadin to synaptic and nuclear sub-compartments. Within the nucleus, afadin is required for increased pERK1/2 which in turn is required for H3S10p. Therefore this represents a mechanism through which estrogens may be able to coordinate both synaptic and nucleosomal events within the same neuronal population.

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Epigenomic Measurements in Brain Tissues

Satterlee¹

2015

Neuroscience in the 21st Century

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Coordinated Nuclear and Synaptic Shuttling of Afadin Promotes Spine Plasticity and Histone Modifications

Cited by 23 publications

References 31 publications

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Cyto-nuclear shuttling of afadin is required for rapid estradiol-mediated modifications of histone H3

Epigenomic Measurements in Brain Tissues

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