14-3-3 Proteins Regulate Protein Kinase A Activity to Modulate Growth Cone Turning Responses

Kent, Christopher B.; Shimada, Tadayuki; Ferraro, Gino B.; Ritter, Brigitte; Yam, Patricia T.; McPherson, Peter S.; Charron, Frédéric; Kennedy, Timothy E.; Fournier, Alyson E.

doi:10.1523/jneurosci.3883-10.2010

Cited by 51 publications

(46 citation statements)

References 48 publications

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“…While 14-3-3 proteins are known to regulate neuronal migration and axonal outgrowth (13, 26, 29, 60), their involvement in synapse formation and spine maintenance has not been fully investigated. Our study provides the first in vivo evidence of 14-3-3’s role in dendritic spine regulation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

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Qiao

Graham

et al. 2015

Biological Psychiatry

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Background The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies have suggested an association between 14-3-3 dysregulation and schizophrenia. Methods We characterized the behavioral and functional changes in the transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. Results We have recently shown that the 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. Here, we report that these 14-3-3 FKO mice display other behavioral deficits which correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. Particularly, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics due to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin. Conclusions Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.

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Section: Discussionmentioning

confidence: 99%

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

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Qiao

Graham

et al. 2015

Biological Psychiatry

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“…p120RasGAP Is Required for Netrin-1-dependent Attraction of Embryonic Cortical Neurons-To determine whether p120RasGAP regulates netrin-1-dependent chemoattraction, we evaluated the effect of p120RasGAP depletion on cortical growth cone turning in response to a netrin-1 gradient using a Dunn chamber turning assay (45,50,51). The growth cones of cortical neurons electroporated with control siRNA turned randomly with no particular preference for any direction when exposed to a control PBS gradient (Fig.…”

Section: Netrin-1 Promotes the Association Of P120rasgap With DCC In mentioning

confidence: 99%

p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

Antoine-Bertrand

Duquette

Alchini

et al. 2016

Journal of Biological Chemistry

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The receptor deleted in colorectal cancer (DCC) mediates the attraction of growing axons to netrin-1 during brain development. In response to netrin-1 stimulation, DCC becomes a signaling platform to recruit proteins that promote axon outgrowth and guidance. The Ras GTPase-activating protein (GAP) p120RasGAP inhibits Ras activity and mediates neurite retraction and growth cone collapse in response to repulsive guidance cues. Here we show an interaction between p120RasGAP and DCC that positively regulates netrin-1-mediated axon outgrowth and guidance in embryonic cortical neurons. In response to netrin-1, p120RasGAP is recruited to DCC in growth cones and forms a multiprotein complex with focal adhesion kinase and ERK. We found that Ras/ERK activities are elevated aberrantly in p120RasGAP-deficient neurons. Moreover, the expression of p120RasGAP Src homology 2 (SH2)-SH3-SH2 domains, which interact with the C-terminal tail of DCC, is sufficient to restore netrin-1-dependent axon outgrowth in p120RasGAP-deficient neurons. We provide a novel mechanism that exploits the scaffolding properties of the N terminus of p120RasGAP to tightly regulate netrin-1/DCC-dependent axon outgrowth and guidance.

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“…For example, it is possible that A-kinase anchoring proteins (Tasken and Aandahl, 2004) mediate spatial targeting of PKA to axonal tips, as has been demonstrated in growth cone guidance of embryonic neurons (Han et al, 2007). Also, 14-3-3 proteins can downregulate PKA activity by stabilizing the interaction between regulatory and catalytic subunits of PKA for growth cone guidance (Kent et al., 2010). Similarly, several protein kinases can control PKA activity via regulating the interaction between its regulatory and catalytic subunits (Braun et al, 1991; Chaturvedi et al, 2006; Houslay, 2006).…”

Section: Discussionmentioning

confidence: 99%

Paxillin phosphorylation counteracts proteoglycan-mediated inhibition of axon regeneration

Kuboyama

Luo

Park

et al. 2013

Experimental Neurology

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In the adult central nervous system, the tips of axons severed by injury are commonly transformed into dystrophic endballs and cease migration upon encountering a rising concentration gradient of inhibitory proteoglycans. However, intracellular signaling networks mediating endball migration failure remain largely unknown. Here we show that manipulation of protein kinase A (PKA) or its downstream adhesion component paxillin can reactivate the locomotive machinery of endballs in vitro and facilitate axon growth after injury in vivo. In dissociated cultures of adult rat dorsal root ganglion neurons, PKA is activated in endballs formed on gradients of the inhibitory proteoglycan aggrecan, and pharmacological inhibition of PKA promotes axon growth on aggrecan gradients most likely through phosphorylation of paxillin at serine 301. Remarkably, pre-formed endballs on aggrecan gradients resume forward migration in response to PKA inhibition. This resumption of endball migration is associated with increased turnover of adhesive point contacts dependent upon paxillin phosphorylation. Furthermore, expression of phosphomimetic paxillin overcomes aggrecan-mediated growth arrest of endballs, and facilitates axon growth after optic nerve crush in vivo. These results point to the importance of adhesion dynamics in restoring endball migration and suggest a potential therapeutic target for axon tract repair.

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14-3-3 Proteins Regulate Protein Kinase A Activity to Modulate Growth Cone Turning Responses

Cited by 51 publications

References 48 publications

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

Paxillin phosphorylation counteracts proteoglycan-mediated inhibition of axon regeneration

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