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FAK is required for suppressing aberrant nuclear mechanotransduction and DNA methylation to prevent vascular injury

ABSTRACT: FAK is required for suppressing aberrant nuclear mechanotransduction and DNA methylation to prevent vascular injury

PROVIDER: PRJNA857070 | ENA |

REPOSITORIES: ENA

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FAK is required for suppressing aberrant nuclear mechanotransduction and DNA methylation to prevent vascular injury

Project description:Mechanical forces generated through adhesive interaction of endothelial cells (EC) influence nuclear envelope and thereby gene transcription. Alteration in EC mechanical forces may trigger aberrant gene transcription leading to lethal vascular diseases including acute lung injury (ALI). The intrinsic pathways that instruct EC nuclear-mechanotransduction and thereby maintains vascular homeostasis remain elusive. We have identified focal adhesion kinase (FAK)-mediated mechanotransduction at the nuclear envelope in instructing transcription of EC-barrier protective genes. We show that loss of EC-FAK increases intracellular tension, which in turn activates nuclear envelop protein emerin, and DNA methyltransferase 3a (DNMT3a). Methylation of transcription factor KLF2 promoter by DNMT3a impaired KLF2 synthesis and transcription of the crucial barrier-maintaining gene, S1PR1. Restoring KLF2 or S1PR1 expression or impairing emerin or DNMT3a activity rescued vascular homeostasis in lungs with FAK-deficient or WT-damaged endothelium. Thus, FAK protects against tension-induced aberrant DNA methylation in EC and is a promising target to prevent ALI.

2022-07-11 | GSE207789 | GEO

CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling

Project description:We report that loss of CCM3/PDCD10 in fibroblasts induces FAK/Src-paxillin signalling driving actomyosin-dependent mechanotransduction leading to YAP/TAZ signalling. In vivo, loss of CCM3 in fibroblasts drives excessive tissue remodelling leading to the dissemination of breast cancer cells to distant organs.

2021-05-06 | GSE155688 | GEO

Tension sensing by FAK governs nuclear mechanotransduction, trancriptome and fate endothelial transcriptome and fate

Project description:Endothelial cell (EC) attachment to the matrix and adjacent cells generates a mechanical environment that maintains a restrictive barrier against the uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Here, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK-deleted EC, increased EC tension activated DNMT3a, which induced methylation of the KLF2 promoter leading to impaired synthesis of KLF2 and restrictive EC transcriptome, including S1PR1. FAK suppressed DNMT3a activity by restricting the tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Inhibiting emerin phosphorylation or DNMT3a activity in damaged lungs enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype. Our works reveal a paradigm whereby FAK sensing of tension transmission to the nucleus maintains restrictive EC transcriptome and lung homeostasis.

2022-08-28 | GSE212037 | GEO

Role of FAK, dominant-negative FAK, FAK-CD and FAKsiRNA in MCF-7 human breast cancer cell tumorigenesis

Project description:Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in proliferation, motility, adhesion, invasion, angiogenesis, and survival signaling. Focal adhesion kinase has been shown to be overexpressed in many types of tumors, including breast cancer at early stages of tumorigenesis. To study the biological role of FAK in breast tumorigenesis, we used FAKsiRNA to down-regulate FAK in MCF-7 cell lines.

2009-08-17 | GSE11581 | GEO

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [KMF parental, KMF clone KT13 (FAK-/-), KT13 + GFP-FAK, KT13 + GFP-FAK R454, and KT13 + deltaGSK beta-catenin]

Project description:Gene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-b-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/b-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.

2019-07-01 | GSE129098 | GEO

Next generation sequencing comparing effects of FFSS, FAK inhibitor and FAK gene deletion.

Project description:Purpose: The goals of this study are to compare the effect of FFSS, FAK inhibitor, and FAK gene deletion on gene expression of NGS-derived RNA-sequencing.

2019-10-31 | GSE139604 | GEO

pCMV-FRNK/pCMV-FAK vs pCMV-FAK in CTL

Project description:CMV-driven inhibition of FAK in soleus muscle was compared vs contralateral muscle

2009-12-31 | GSE12744 | GEO

ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning

Project description:Precise vascular patterning is critical for normal growth and development. The ERG transcription factor drives Delta like ligand 4 (DLL4)/Notch signalling and is thought to act as pivotal regulators of endothelial cell (EC) dynamics and developmental angiogenesis. However, molecular regulation of ERG activity remains obscure. Using a series of EC specific Focal Adhesion Kinase (FAK)-knockout (KO) and point-mutant FAK-knockin mice, we show that loss of ECFAK, its kinase activity or phosphorylation at FAK-Y397, but not FAK-Y861, reduces ERG and DLL4 expression levels together with concomitant aberrations in vascular patterning. Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins identified that endothelial nuclear-FAK interacts with the de-ubiquitinase USP9x and the ubiquitin ligase TRIM25 enzymes. Further in silico analysis corroborates that ERG interacts with USP9x and TRIM25. Moreover, ERG levels are reduced in FAKKO ECs via a ubiquitin-mediated post-translational modification programme involving USP9x and TRIM25. Re-expression of ERG in vivo and in vitro rescues the aberrant vessel sprouting defects observed in the absence of ECFAK. Our findings identify ECFAK as a regulator of retinal vascular patterning by controlling ERG protein degradation via TRIM25/USP9x.

2022-07-05 | PXD033447 | Pride

siRNA profiling if human MCF-7 cell line to investigate the role of FAK, dominant-negative FAK, FAK-CD and FAKsiRNA in MCF-7 human breast cancer cell tumorigenesis

2009-08-22 | E-GEOD-11581 | biostudies-arrayexpress

Gene profile of breast cancer tumors with low and high FAK expression

Project description:The gene expression profiles were identified in breast cancer tumors with different level of FAK three tumors with low FAK expression identified by IHC and 3 tumors with high FAK expression. 2 triple-negative with low and one triple negative with high FAK expression was among these 6 samples

2014-02-01 | E-GEOD-53618 | biostudies-arrayexpress

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