MeHg affects the activation of FAK, Src, Rac1 and Cdc42, critical proteins for cell movement in PDGF-stimulated SH-SY5Y neuroblastoma cells

Hernández, A.; Reyes, Vilcy; Albores-García, Damaris; Gómez, Rocío; Calderón-Aranda, Emma S.

doi:10.1016/j.tox.2017.11.019

Cited by 10 publications

(6 citation statements)

References 71 publications

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“…However, as illustrated in Figure 4B, in response to PDGF-BB treatment for 24 h, there was an improvement in the activation of Cdc42 (0.78 ± 0.03 vs. 1.21 ± 0.05, p < 0.05) but not Rac1. Although some studies have reported that PDGF-BB can induce Rac1 activation in different in vitro models [29], our study showed that Rac1 was transiently activated between 0 and 24 h and then returned to the normal level at 12 h (Figure S2). The increased activation of Cdc42 induced by PDGF-BB was significantly inhibited by crenolanib (1.21 ± 0.05 vs. 0.81 ± 0.04, p < 0.05).…”

Section: Pdgf-bb Promotes Rhogdi1-cdc42 Interaction and Thus Cdc42 Activation By Its Receptorcontrasting

confidence: 56%

RhoGDI1-Cdc42 Signaling Is Required for PDGF-BB-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Neointima Formation

Liang

Guan

et al. 2021

Biomedicines

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RhoGTPase is involved in PDGF-BB-mediated VSMC phenotypic modulation. RhoGDIs are key factors in regulating RhoGTPase activation. In the present study, we investigated the regulatory effect of RhoGDI1 on the activation of RhoGTPase in VSMC transformation and neointima formation. Western blot and co-immunoprecipitation assays showed that the PDGF receptor inhibition by crenolanib promoted RhoGDI1 polyubiquitination and degradation. Inhibition of RhoGDI1 degradation via MG132 reversed the decrease in VSMC phenotypic transformation. In addition, RhoGDI1 knockdown significantly inhibited VSMC phenotypic transformation and neointima formation in vitro and in vivo. These results suggest that PDGF-BB promotes RhoGDI1 stability via the PDGF receptor and induces the VSMC synthetic phenotype. The co-immunoprecipitation assay showed that PDGF-BB enhanced the interaction of RhoGDI1 with Cdc42 and promoted the activation of Cdc42; these enhancements were blocked by crenolanib and RhoGDI1 knockdown. Moreover, RhoGDI1 knockdown and crenolanib pretreatment prevented the localization of Cdc42 to the plasma membrane (PM) to activate and improve the accumulation of Cdc42 on endoplasmic reticulum (ER). Furthermore, Cdc42 inhibition or suppression significantly reduced VSMC phenotypic transformation and neointima formation in vitro and in vivo. This study revealed the novel mechanism by which RhoGDI1 stability promotes the RhoGDI1-Cdc42 interaction and Cdc42 activation, thereby affecting VSMC phenotypic transformation and neointima formation.

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Section: Pdgf-bb Promotes Rhogdi1-cdc42 Interaction and Thus Cdc42 Activation By Its Receptorcontrasting

confidence: 56%

RhoGDI1-Cdc42 Signaling Is Required for PDGF-BB-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Neointima Formation

Liang

Guan

et al. 2021

Biomedicines

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“…The FAK-centered integrin signaling pathway regulates two pathways; one is the Ras/mitogen-activated protein kinase (MAPK) pathway and the other is the FAK signaling pathway, which is independent of c-Src interaction. Activation of the Ras/MAPK pathway by FAK requires participation of Src ( 28 ). To verify which pathway is involved in PHEV-induced early cofilin phosphorylation, we performed the following experiments.…”

Section: Resultsmentioning

confidence: 99%

“…9E ). Platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) significantly activated intracellular Rac1 and Cdc42, respectively ( 28 , 32 ). The cells were treated with PDGF and EGF to test the specificity of the established method.…”

Section: Resultsmentioning

confidence: 99%

Porcine Hemagglutinating Encephalomyelitis Virus Activation of the Integrin α5β1-FAK-Cofilin Pathway Causes Cytoskeletal Rearrangement To Promote Its Invasion of N2a Cells

Liu

Guan

et al. 2019

J Virol

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Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic virus that causes diffuse neuronal infection with neurological damage and high mortality. Virus-induced cytoskeletal dynamics are thought to be closely related to this type of nerve damage. Currently, the regulation pattern of the actin cytoskeleton and its molecular mechanism remain unclear when PHEV enters the host cells. Here, we demonstrate that entry of PHEV into N2a cells induces a biphasic remodeling of the actin cytoskeleton and a dynamic change in cofilin activity. Viral entry is affected by the disruption of actin kinetics or alteration of cofilin activity. PHEV binds to integrin ␣5␤1 and then initiates the integrin ␣5␤1-FAK signaling pathway, leading to virus-induced early cofilin phosphorylation and F-actin polymerization. Additionally, Ras-related C3 botulinum toxin substrate 1 (Rac1), cell division cycle 42 (Cdc42), and downstream regulatory gene p21-activated protein kinases (PAKs) are recruited as downstream mediators of PHEV-induced dynamic changes of the cofilin activity pathway. In conclusion, we demonstrate that PHEV utilizes the integrin ␣5␤1-FAK-Rac1/Cdc42-PAK-LIMK-cofilin pathway to cause an actin cytoskeletal rearrangement to promote its own invasion, providing theoretical support for the development of PHEV pathogenic mechanisms and new antiviral targets. IMPORTANCE PHEV, a member of the Coronaviridae family, is a typical neurotropic virus that primarily affects the nervous system of piglets to produce typical neurological symptoms. However, the mechanism of nerve damage caused by the virus has not been fully elucidated. Actin is an important component of the cytoskeleton of eukaryotic cells and serves as the first obstacle to the entry of pathogens into host cells. Additionally, the morphological structure and function of nerve cells depend on the dynamic regulation of the actin skeleton. Therefore, exploring the mechanism of neuronal injury induced by PHEV from the perspective of the actin cytoskeleton not only helps elucidate the pathogenesis of PHEV but also provides a theoretical basis for the search for new antiviral targets. This is the first report to define a mechanistic link between alterations in signaling from cytoskeleton pathways and the mechanism of PHEV invading nerve cells.

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“…Previously, it was shown that FAK regulates cytoskeletal reorganization in response to many integrins ( Cary and Guan, 1999 ) and that FAK–Src complexes promote the activation of Rac1 and Cdc42, two GTPases involved in the remodeling of the actin cytoskeletal network ( Hernandez et al, 2018 ). However, we found that only CDC42 was effective in inducing Pak1 kinase in cells that had been previously stimulated to enhance periostin signaling pathways ( Ghatak et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Periostin/Filamin-A: A Candidate Central Regulatory Axis for Valve Fibrogenesis and Matrix Compaction

Misra

Ghatak

Rodríguez

et al. 2021

Front. Cell Dev. Biol.

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BackgroundDiscoveries in the identification of transcription factors, growth factors and extracellular signaling molecules have led to the detection of downstream targets that modulate valvular tissue organization that occurs during development, aging, or disease. Among these, matricellular protein, periostin, and cytoskeletal protein filamin A are highly expressed in developing heart valves. The phenotype of periostin null indicates that periostin promotes migration, survival, and differentiation of valve interstitial cushion cells into fibroblastic lineages necessary for postnatal valve remodeling/maturation. Genetically inhibiting filamin A expression in valve interstitial cushion cells mirrored the phenotype of periostin nulls, suggesting a molecular interaction between these two proteins resulted in poorly remodeled valve leaflets that might be prone to myxomatous over time. We examined whether filamin A has a cross-talk with periostin/signaling that promotes remodeling of postnatal heart valves into mature leaflets.ResultsWe have previously shown that periostin/integrin-β1 regulates Pak1 activation; here, we revealed that the strong interaction between Pak1 and filamin A proteins was only observed after stimulation of VICs with periostin; suggesting that periostin/integrin-β-mediated interaction between FLNA and Pak1 may have a functional role in vivo. We found that FLNA phosphorylation (S2152) is activated by Pak1, and this interaction was observed after stimulation with periostin/integrin-β1/Cdc42/Rac1 signaling; consequently, FLNA binding to Pak1 stimulates its kinase activity. Patients with floppy and/or prolapsed mitral valves, when genetically screened, were found to have point mutations in the filamin A gene at P637Q and G288R. Expression of either of these filamin A mutants failed to increase the magnitude of filamin A (S2152) expression, Pak1-kinase activity, actin polymerization, and differentiation of VICs into mature mitral valve leaflets in response to periostin signaling.ConclusionPN-stimulated bidirectional interaction between activated FLNA and Pak1 is essential for actin cytoskeletal reorganization and the differentiation of immature VICs into mature valve leaflets.

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MeHg affects the activation of FAK, Src, Rac1 and Cdc42, critical proteins for cell movement in PDGF-stimulated SH-SY5Y neuroblastoma cells

Cited by 10 publications

References 71 publications

RhoGDI1-Cdc42 Signaling Is Required for PDGF-BB-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Neointima Formation

RhoGDI1-Cdc42 Signaling Is Required for PDGF-BB-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Neointima Formation

Porcine Hemagglutinating Encephalomyelitis Virus Activation of the Integrin α5β1-FAK-Cofilin Pathway Causes Cytoskeletal Rearrangement To Promote Its Invasion of N2a Cells

Periostin/Filamin-A: A Candidate Central Regulatory Axis for Valve Fibrogenesis and Matrix Compaction

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