FAK signalling mediates NF-κB activation by mechanical stress in cardiac myocytes

Crosara-Alberto, Daniella P.; Inoue, Rosana Yuri; Costa, Caetano da

doi:10.1016/j.cca.2009.01.023

Cited by 26 publications

(17 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[22][23][24] The activated FAK-Src complex can initiate a cascade of phosphorylation events to trigger multiple intracellular signaling pathways. To further determine whether the decreased FAK activity affects Src, we examined total Src protein expression and Src phosphorylation.…”

Section: Protein Expression and Activity Of Src Are Down-regulated Inmentioning

confidence: 99%

“…20 As shown in Figure 1, FAK is activated by receiving signaling from the upstream integrins; FAK undergoes autophosphorylation at Y397, which generates a binding site for Src via the SH2 domain and activates Src. [21][22][23] The activated Src further phosphorylates FAK on other tyrosine residues (Y576/577 and Y925), leading to the full activation of FAK. 22,23 The activated FAK-Src complex then initiates a cascade of phosphorylation events and new protein-protein interactions to trigger multiple intracellular signaling pathways.…”

mentioning

confidence: 99%

“…[21][22][23] The activated Src further phosphorylates FAK on other tyrosine residues (Y576/577 and Y925), leading to the full activation of FAK. 22,23 The activated FAK-Src complex then initiates a cascade of phosphorylation events and new protein-protein interactions to trigger multiple intracellular signaling pathways. Many studies 24 have shown that FAK facilitates the generation of integrin-stimulated signals to downstream targets, such as the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase (ERK) 2 and the c-Jun N-terminal kinase (JNK)-MEK cascades.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Wei

Malik

Sheikh

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Recent studies suggest that one of the major pathways to the pathogenesis of autism is reduced cell migration. Focal adhesion kinase (FAK) has an important role in neural migration, dendritic morphological characteristics, axonal branching, and synapse formation. The FAK-Src complex, activated by upstream reelin and integrin ␤1, can initiate a cascade of phosphorylation events to trigger multiple intracellular pathways, including mitogen-activated protein kinaseextracellular signal-regulated kinase and phosphatidylinositol 3-kinase-Akt signaling. In this study, by using B lymphoblasts as a model, we tested whether integrin ␤1 and FAK-Src signaling are abnormally regulated in autism and whether abnormal FAK-Src signaling leads to defects in B-lymphoblast adhesion, migration, proliferation, and IgG production. To our knowledge, for the first time, we show that protein expression levels of both integrin ␤1 and FAK are significantly decreased in autistic lymphoblasts and that Src protein expression and the phosphorylation of an active site (Y416) are also significantly decreased. We also found that lymphoblasts from autistic subjects exhibit significantly decreased migration, increased adhesion properties, and an impaired capacity for IgG production. The overexpression of FAK in autistic lymphoblasts countered the adhesion and migration defects. In addition, we demonstrate that FAK mediates its effect through the activation of Src, phosphatidylinositol 3-kinase-Akt, and mitogen-activated protein kinase signaling cascades and that paxillin is also likely involved in the regulation of adhesion and migration in autistic lymphoblasts. Autism is a severe neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Susceptibility to autism is clearly attributable to the interplay of genetic and environmental factors, 1-10 but the etiology of this disorder is unknown and no biomarkers have yet been proved characteristic of autism. Recent research 11 is beginning to depict three major pathways as being potentially involved in the pathogenesis of autism (ie, reduced cell migration, excitatory-inhibitory imbalance, and abnormal synaptogenesis). The reelin protein encoded by the RELN gene plays a pivotal role in neuronal cell migration and the prenatal development of neural connections.12 Reelin has coexpressed with HAR1F, which is a novel RNA gene expressed specifically in Cajal-Retzius neurons in the developing human neocortex from gestational week 7 to 19 (a crucial period for cortical neuron specification and migration). 13 Linkage between RELN and autism is a replicated genetic finding in autism research, and reelin has been reduced in the serum and brain specimens of autistic subjects.14,15 Reelin can act through ␣3␤1 integrins and exert proteolytic activity on extracellular matrix (ECM) proteins, which are crucial for neuronal migration. 16 Most recently, emerging evidence 17 indicates that synaptic cell adhesion pathways are disrupted in some

show abstract

Section: Protein Expression and Activity Of Src Are Down-regulated Inmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Wei

Malik

Sheikh

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…35 Costa et al reported that FAK signaling coordinates cardiac myocyte NF-kB activation in response to mechanical stress. 10 NF-kB signal transduction pathway was found significantly represented in GePS analysis. It may be very early-activated signal transduction pathway in low level mechanical stimulation.…”

Section: Discussionmentioning

confidence: 97%

Genome-Wide Gene Expression Analysis of NIH 3T3 Cell Line Under Mechanical Stimulation

Demirci

Trzewik

et al. 2010

Cel. Mol. Bioeng.

View full text Add to dashboard Cite

Cyclic mechanical stretching induces biological and biomechanical response in cells. These responses are firstly determined by gene expression regulation in the cells of tissue. A method based on the CellDrum Ò Technology provided the environment for cyclic mechanical stimulation of NIH 3T3 cells in vitro. Cells were cultured on a silicone membrane. mRNA expression levels of the genes Egr1, Fgfr2, Tp53, Itgb3, and Itgb5 was evaluated by real-time PCR at stimulation times ranging from 5 min to 12 h with a cyclic strain of 0.25% at 0.25 Hz in order to decide which time period was most suitable for a subsequent detailed profiling. The genome-wide expression profile of NIH 3T3 cells was carried out by whole mouse genome microarrays. The mRNA expression levels of most genes tested were significantly changed after 1 h of mechanical stimulation. Subsequently, the mRNA samples of the 1-h stretched cells were hybridized to obtain a gene expression profile using microarrays. Real-time PCR results are shown to agree with the microarray results. The early response genes, such as Egr1, Egr2, Fos, Myc, Rela, Fas, Egfr1, and Fgfr2 playing a role in stretch activation of the signal transduction pathways were significantly up-regulated, whereas the only significantly down-regulated gene is Tfrc. Low level of mechanical stimulation was found to effect the expression of early responsive genes initiates alteration of NIH 3T3 behaviors to control the homeostasis of the fibroblasts.

show abstract

“…NF-κB nuclear translocation is activated by FSS in osteoblasts [112] and requires FAK [46]. Similarly, FAK mediates NF-κB signaling in endothelial cells in response to FSS [113] and in cardiac myocytes in response to mechanical strain [114]. The precise details of how FAK and NF-κB may interact as part of a “STOP” mechanosome complex remain to be determined.…”

Section: The Mechanosome Revisited: Expansion Revision and Supportmentioning

confidence: 99%

The Load-Bearing Mechanosome Revisited

Bidwell

Pavalko

2010

Clinic Rev Bone Miner Metab

View full text Add to dashboard Cite

We introduced the mechanosome hypothesis in 2003 as a heuristic model for investigating mechanotransduction in bone (Pavalko et al., J Cell Biochem, 2003, 88(1):104–112). This model suggested specific approaches for investigating how mechanical information is conveyed from the membrane of the sensor bone cell to the target genes and how this transmitted information from the membrane is converted into changes in transcription. The key concepts underlying the mechanosome hypothesis are that load-induced deformation of bone deforms the sensor cell membrane; embedded in the membrane are the focal adhesion and cadherin–catenin complexes, which in turn are physically connected to the chromatin via a solid-state scaffold. The physical stimulation of the membrane launches multiprotein complexes (mechanosomes) from the adhesion platforms while concomitantly tugging target genes into position for contact with the incoming mechanosomes, the carriers of the mechanical information to the nucleus. The mechanosome is comprised of an adhesion-associated protein and a nucleocytoplasmic shuttling transcription factor. Upon arrival at the target gene, mechanosomes alter DNA conformation and thus influence the interactions between trans-acting proteins along the gene, changing gene activity. Here, we update significant progress related to the mechanosome concept since publication of our original hypothesis. The launching of adhesion- and cytoskeletal-associated proteins into the nucleus toward target genes appears to be a common mechanism for regulating cell response to changes in its mechanical microenvironment.

show abstract

FAK signalling mediates NF-κB activation by mechanical stress in cardiac myocytes

Cited by 26 publications

References 30 publications

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Genome-Wide Gene Expression Analysis of NIH 3T3 Cell Line Under Mechanical Stimulation

The Load-Bearing Mechanosome Revisited

Contact Info

Product

Resources

About