Neuropilin-1 regulates a new VEGF-induced gene, Phactr-1, which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells

Allain, Barbara; Jarray, Rafika; Borriello, Lucia; Leforban, Bertrand; Dufour, Sylvie; Liu, Wangqing; Pamonsinlapatham, Perayot; Bianco, Sara; Larghero, Jérôme; Hadj-Slimane, Réda; Garbay, Christiane; Raynaud, Françoise; Lepelletier, Yves

doi:10.1016/j.cellsig.2011.09.003

Cited by 63 publications

(53 citation statements)

References 35 publications

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“…This was confirmed through the observation that abolishing PHACTR1 expression or overexpressing miR-584 resulted in a loss of the formation of filopodia, which are necessary for cell motility, by TGF-␤. Moreover, a recent study highlighted a role for PHACTR1 in endothelial cells, where it is required for the control of cycles of actin polymerization and depolymerization (40). Combined with our study, these data may indicate that PHACTR1 plays a central role in regulating cell migration in multiple tissue and cell types, including breast cancer.…”

Section: Volume 288 • Number 17 • April 26 2013supporting

confidence: 61%

MicroRNA-584 and the Protein Phosphatase and Actin Regulator 1 (PHACTR1), a New Signaling Route through Which Transforming Growth Factor-β Mediates the Migration and Actin Dynamics of Breast Cancer Cells

Fils-Aimé

Dai

Guo

et al. 2013

Journal of Biological Chemistry

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Background: TGF-␤ promotes cell migration in advanced breast cancer. Results: TGF-␤ down-regulates miR-584, leading to a PHACTR1 overexpression, and both are involved in cell migration and actin reorganization. Conclusion:The regulation of miR-584 and regulation of its novel target PHACTR1 are necessary steps for breast cancer cell migration. Significance: MicroRNAs offer an interesting therapeutic target in the treatment of advanced breast malignancy.

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Section: Volume 288 • Number 17 • April 26 2013supporting

confidence: 61%

MicroRNA-584 and the Protein Phosphatase and Actin Regulator 1 (PHACTR1), a New Signaling Route through Which Transforming Growth Factor-β Mediates the Migration and Actin Dynamics of Breast Cancer Cells

Fils-Aimé

Dai

Guo

et al. 2013

Journal of Biological Chemistry

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“…[25,26] In contrast to other studies,[26,27] Beaudoin et al reported a lack of evidence for the induction of PHACTR1 expression in endothelial cells with pro-angiogenic (VEGF), pro-inflammatory stimulations or shear stress. [16] Our immunohistochemistry staining of PHACTR1 indicates the presence of PHACTR1 both in endothelial and smooth muscle cells of normal and FMD carotid arteries.…”

Section: Discussionmentioning

confidence: 99%

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance

et al. 2016

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Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10−4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10−10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10−4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development.We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

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“…The subcellular localization of Phactr proteins has not been studied systematically and variable localization patterns ranging from nuclear to cytoplasmic have been reported (Allen et al, 2004;Farghaian et al, 2011;Favot et al, 2005;Kim et al, 2007;Sagara et al, 2009;Sagara et al, 2003;Zhang et al, 2012). Phactr proteins have been implicated in many distinct biological processes, from angiogenesis (Allain et al, 2012;Jarray et al, 2011) to cell spreading, migration (Sagara et al, 2009) and axon elongation (Farghaian et al, 2011), which are also dependent on the actin cytoskeleton. Mice carrying a specific mutation of Phactr4 gene called the humdy exhibit a defect of neural tube and optic fissure closure resulting in anomalies such as exencephaly.…”

Section: Introductionmentioning

confidence: 99%

Actin-regulated feedback loop based on Phactr4, PP1 and cofilin maintains the actin monomer pool

Huet

Rajakylä

Viita

et al. 2013

Journal of Cell Science

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SummaryPhactr proteins bind actin and protein phosphatase 1 (PP1), and are involved in processes ranging from angiogenesis to cell cycle regulation. Phactrs share a highly conserved RPEL domain with the myocardin-related transcription factor (MRTF) family, where actin binding to this domain regulates both the nuclear localization and the activity of these transcription coactivators. We show here that in contrast to MRTF-A, the RPEL domain is dispensable for the subcellular localization of Phactr4. Instead, we find the domain facilitating competitive binding of monomeric actin and PP1 to Phactr4. Binding of actin to Phactr4 influences the activity of PP1 and the phosphorylation status of one of its downstream targets, cofilin. Consequently, at low actin monomer levels, Phactr4 guides PP1 to dephosphorylate cofilin. This active form of cofilin is then able to sever and depolymerize actin filaments and thus restore the actin monomer pool. Accordingly, our data discloses the central role of Phactr4 in a feedback loop, where actin monomers regulate their own number via the activation of a key regulator of actin dynamics. Depending on the protein context, the RPEL domain can thus elicit mechanistically different responses to maintain the cellular actin balance.

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Neuropilin-1 regulates a new VEGF-induced gene, Phactr-1, which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells

Cited by 63 publications

References 35 publications

MicroRNA-584 and the Protein Phosphatase and Actin Regulator 1 (PHACTR1), a New Signaling Route through Which Transforming Growth Factor-β Mediates the Migration and Actin Dynamics of Breast Cancer Cells

MicroRNA-584 and the Protein Phosphatase and Actin Regulator 1 (PHACTR1), a New Signaling Route through Which Transforming Growth Factor-β Mediates the Migration and Actin Dynamics of Breast Cancer Cells

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance

Actin-regulated feedback loop based on Phactr4, PP1 and cofilin maintains the actin monomer pool

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