Brefeldin A-inhibited Guanine Exchange Factor 2 Regulates Filamin A Phosphorylation and Neuronal Migration

Zhang, Jingping; Neal, Jason; Lian, Gewei; Shi, Bingxing; Ferland, Russell J.; Sheen, Volney L.

doi:10.1523/jneurosci.1063-12.2012

Cited by 42 publications

(59 citation statements)

References 44 publications

(60 reference statements)

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“…7I). These results agree with previous data where Myc-tagged FLNa-S2152A localizes with actin fibers at the cell surface, whereas phosphorylation of FLNa directs it towards the cytoplasm of CHP100 cells (Zhang et al, 2012). We also showed here that CCR2B and β2AR signaling can trigger phosphorylation of FLNa at S2152.…”

Section: Discussionsupporting

confidence: 93%

“…FLNa is regulated by phosphorylation at S2152 by many protein kinases, and this phosphorylation has a direct effect on its function in regulating a variety of cytoskeleton-related events (Hastie et al, 1997;Muriel et al, 2011;Travis et al, 2004;Zhang et al, 2012). Here, we show that phosphorylation of the same residue is necessary for efficient recycling of CCR2B and β2AR.…”

Section: Discussionmentioning

confidence: 71%

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Phosphorylation of filamin A regulates chemokine receptor CCR2 recycling

Pons

Izquierdo

Andreu-Carbó

et al. 2017

Journal of Cell Science

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Proper endosomal trafficking of ligand-activated G-protein-coupled receptors (GPCRs) is essential to spatiotemporally tune their physiological responses. For the monocyte chemoattractant receptor 2 (CCR2B; one of two isoforms encoded by CCR2), endocytic recycling is important to sustain monocyte migration, whereas filamin A (FLNa) is essential for CCL2-induced monocyte migration. Here, we analyze the role of FLNa in the trafficking of CCR2B along the endocytic pathway. In FLNa-knockdown cells, activated CCR2B accumulated in enlarged EEA-1-positive endosomes, which exhibited slow movement and fast fluorescence recovery, suggesting an imbalance between receptor entry and exit rates. Utilizing super-resolution microscopy, we observed that FLNa-GFP, CCR2B and β2-adrenergic receptor (β2AR) were present in actin-enriched endosomal microdomains. Depletion of FLNa decreased CCR2B association with these microdomains and concomitantly delayed CCR2B endosomal traffic, without apparently affecting the number of microdomains. Interestingly, CCR2B and β2AR signaling induced phosphorylation of FLNa at residue S2152, and this phosphorylation event was contributes to sustain receptor recycling. Thus, our data strongly suggest that CCR2B and β2AR signals to FLNa to stimulate its endocytosis and recycling to the plasma membrane.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 71%

Phosphorylation of filamin A regulates chemokine receptor CCR2 recycling

Pons

Izquierdo

Andreu-Carbó

et al. 2017

Journal of Cell Science

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“…7). In the case of filamin, a broad range of filamin ligands, which correspond to diverse cellular events mediated by this phosphorylation event such as platelet aggregation (39), cytoskeletal rearrangement (41), mechanoprotection (40), cancer metastasis (38) and defective neuronal migration (42), were found to promote filamin Ser 2152 phosphorylation. It is conceivable that different ligands, depending on their spatiotemporal localization with filamin, may promote its phosphorylation and modulate specific downstream signaling events.…”

Section: Discussionmentioning

confidence: 99%

A Mechanism of Global Shape-dependent Recognition and Phosphorylation of Filamin by Protein Kinase A

Ithychanda

Mohan

Zhu

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism of filamin Ser 2152 phosphorylation by PKA is unclear. Results: Autoinhibitory filamin is resistant to phosphorylation despite exposed Ser 2152 , but ligand binding alters the filamin conformation, triggering PKA recognition. Conclusion: Filamin Ser2152 phosphorylation is conformation-dependent on ligand binding. Significance: The overall conformation of substrate, not just the exposed phosphorylation site, regulates the kinase substrate recognition in signaling.

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“…The actin binding FlnA protein forms homodimers that regulate the cytoskeleton through interactions via multiple proteins, thereby promoting actin changes at the cell periphery to maintain cell shape. FlnA regulation of actin may directly affect migration and maintenance of the neuroependyma (Carreno et al, 2004;Smythe and Ayscough, 2006). ARFGEF2 encodes for brefeldin-A-inhibited guanine exchange factor-2 (BIG2; .…”

Section: Introductionmentioning

confidence: 99%

Filamin A Regulates Neuronal Migration through Brefeldin A-Inhibited Guanine Exchange Factor 2-Dependent Arf1 Activation

et al. 2013

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Periventricular heterotopias is a malformation of cortical development, characterized by ectopic neuronal nodules around ventricle lining and caused by an initial migration defect during early brain development. Human mutations in the Filamin A (FLNA) and ADP-ribosylation factor guanine exchange factor 2 [ARFGEF2; encoding brefeldin-A-inhibited guanine exchange factor-2 (BIG2)] genes give rise to this disorder. Previously, we have reported that Big2 inhibition impairs neuronal migration and binds to FlnA, and its loss promotes FlnA phosphorylation. FlnA phosphorylation dictates FlnA–actin binding affinity and consequently alters focal adhesion size and number to effect neuronal migration. Here we show that FlnA loss similarly impairs migration, reciprocally enhances Big2 expression, but also alters Big2 subcellular localization in both null and conditional FlnA mice. FlnA phosphorylation promotes relocalization of Big2 from the Golgi toward the lipid ruffles, thereby activating Big2-dependent Arf1 at the cell membrane. Loss of FlnA phosphorylation or Big2 function impairs Arf1-dependent vesicle trafficking at the periphery, and Arf1 is required for maintenance of cell–cell junction connectivity and focal adhesion assembly. Loss of Arf1 activity disrupts neuronal migration and cell adhesion. Collectively, these studies demonstrate a potential mechanism whereby coordinated interactions between actin (through FlnA) and vesicle trafficking (through Big2-Arf) direct the assembly and disassembly of membrane protein complexes required for neuronal migration and neuroependymal integrity.

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Brefeldin A-inhibited Guanine Exchange Factor 2 Regulates Filamin A Phosphorylation and Neuronal Migration

Cited by 42 publications

References 44 publications

Phosphorylation of filamin A regulates chemokine receptor CCR2 recycling

Phosphorylation of filamin A regulates chemokine receptor CCR2 recycling

A Mechanism of Global Shape-dependent Recognition and Phosphorylation of Filamin by Protein Kinase A

Filamin A Regulates Neuronal Migration through Brefeldin A-Inhibited Guanine Exchange Factor 2-Dependent Arf1 Activation

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