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CRK proteins are essential for SRC/FAK signaling in EMT

ABSTRACT: Novel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial-mesenchymal transition and colorectal cancer aggressiveness

PROVIDER: PRJEB36353 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3958880_1.fastq.gz	Fastqsanger.gz
	ERR3958880_2.fastq.gz	Fastqsanger.gz
	ERR3958871_1.fastq.gz	Fastqsanger.gz
	ERR3958871_2.fastq.gz	Fastqsanger.gz
	ERR3958881_1.fastq.gz	Fastqsanger.gz

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Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks

Project description:Here, using mouse squamous cell carcinoma cells, we report a completely new function for the autophagy protein Ambra1 as the first described ‘spatial rheostat’ controlling the Src/FAK pathway. Ambra1 regulates the targeting of active phospho-Src away from focal adhesions into autophagic structures that cancer cells use to survive adhesion stress. Ambra1 binds to both FAK and Src in cancer cells. When FAK is present, Ambra1 is recruited to focal adhesions, promoting FAK-regulated cancer cell direction-sensing and invasion. However, when Ambra1 cannot bind to FAK, abnormally high levels of phospho-Src and phospho-FAK accumulate at focal adhesions, positively regulating adhesion and invasive migration. Spatial control of active Src requires the trafficking proteins Dynactin 1 and IFITM3, which we identified as Ambra1 binding partners by interaction proteomics. We conclude that Ambra1 is a core component of an intracellular trafficking network linked to tight spatial control of active Src and FAK levels, and so crucially regulates their cancer-associated biological outputs.

2017-04-04 | PXD006002 | Pride

Transcription profiling of mouse fibroblasts derived from p130Cas exon 2-specific knockout mice.

Project description:p130Cas (Cas, Crk-associated substrate) is an adaptor molecule composed of an N-terminal Src homology 3 (SH3) domain, a substrate domain (SD), and a C-terminal Src binding domain (SBD). The SH3 domain of Cas has been shown to associate with various signaling molecules, including focal adhesion kinase (FAK), but its role in cellular function remains unclear. To address this issue, we established and analyzed primary fibroblasts derived from mice expressing a truncated Cas lacking the exon 2 encoding the SH3 domain (Cas exon 2â/â). In comparison to wild-type (Cas exon 2+/+) cells, Cas exon 2â/â primary fibroblasts showed delayed migration in wound healing and reduced spreading on fibronectin (FN), which would be due to reduced complex formation of Cas exon 2â/â with FAK and CrkII and also to impaired localization of Cas exon 2â/â to focal adhesions on FN. In addition, to analyze downstream signaling pathway regulated by Cas exon 2, we compared gene expression profiles between Cas exon 2+/+ and Cas exon 2â/â cells by a microarray analysis. Interestingly, we found that Cas exon 2-deficiency upregulated expression of CXC Chemokine Receptor-4 (CXCR4), CC Chemokine Receptor-5 (CCR5), and thrombospondin 4, which are implicated in cell motility and adhesion. These results define the role of Cas SH3-encoding exon in cell motility, FAK/Cas/CrkII complex formation, recruitment of Cas to focal adhesions, and regulation of cell adhesion-associated gene expression in primary fibroblasts. Experiment Overall Design: RNA samples extracted from Cas exon 2+/+, Cas exon 2+/â, and Cas exon 2â/â fibroblasts (12.5dpc, two embryos for each genotype) were labeled and hybridized on Affymetrix microarray. Gene expression patterns of Cas exon 2â/â fibroblasts were compared with those of Cas exon 2+/+ and Cas exon 2+/â cells.

2008-06-16 | E-GEOD-8357 | biostudies-arrayexpress

Functional analysis of exon 2 of p130Cas in fibroblasts derived from exon 2-specific knockout mice.

Project description:p130Cas (Cas, Crk-associated substrate) is an adaptor molecule composed of an N-terminal Src homology 3 (SH3) domain, a substrate domain (SD), and a C-terminal Src binding domain (SBD). The SH3 domain of Cas has been shown to associate with various signaling molecules, including focal adhesion kinase (FAK), but its role in cellular function remains unclear. To address this issue, we established and analyzed primary fibroblasts derived from mice expressing a truncated Cas lacking the exon 2 encoding the SH3 domain (Cas exon 2∆/∆). In comparison to wild-type (Cas exon 2+/+) cells, Cas exon 2∆/∆ primary fibroblasts showed delayed migration in wound healing and reduced spreading on fibronectin (FN), which would be due to reduced complex formation of Cas exon 2∆/∆ with FAK and CrkII and also to impaired localization of Cas exon 2∆/∆ to focal adhesions on FN. In addition, to analyze downstream signaling pathway regulated by Cas exon 2, we compared gene expression profiles between Cas exon 2+/+ and Cas exon 2∆/∆ cells by a microarray analysis. Interestingly, we found that Cas exon 2-deficiency upregulated expression of CXC Chemokine Receptor-4 (CXCR4), CC Chemokine Receptor-5 (CCR5), and thrombospondin 4, which are implicated in cell motility and adhesion. These results define the role of Cas SH3-encoding exon in cell motility, FAK/Cas/CrkII complex formation, recruitment of Cas to focal adhesions, and regulation of cell adhesion-associated gene expression in primary fibroblasts. Keywords: SH3-encoding exon, p130Cas

2007-12-31 | GSE8357 | 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

Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition.

Project description:Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, "EGFR-addicted" cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erlotinib-resistant cells, we performed a small molecule screen of ~200 established anti-cancer agents using the EGFR mutant NSCLC HCC827 cell line and a corresponding mesenchymal derivative line. The mesenchymal cells were more resistant to most tested agents; however, a small number of agents showed selective growth inhibitory activity against the mesenchymal cells, with the most potent being the Abl/Src inhibitor, dasatinib. Analysis of the tyrosine phospho-proteome revealed several Src/FAK pathway kinases that were differentially phosphorylated in the mesenchymal cells, and RNAi depletion of the core Src/FAK pathway components in these mesenchymal cells caused apoptosis. These findings reveal a novel role for Src/FAK pathway kinases in drug resistance and identify dasatinib as a potential therapeutic for treatment of erlotinib resistance associated with EMT.

| S-EPMC4202126 | biostudies-literature

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

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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