Background Focal adhesion Kinase (FAK) is a nonreceptor proteins tyrosine kinase that is overexpressed in tumors and plays a significant role in tumor survival and PD318088 metastasis. in matched main tumors by Spearman correlation analysis. In addition a strong positive correlation was observed between high FAK expression and shorter overall survival and progression free survival in patients with metastatic tumors. Conclusions The data demonstrate a high potential for FAK as a therapeutic target especially in triple-negative breast cancer patients with high FAK expression. Rabbit Polyclonal to BLNK (phospho-Tyr84). (not shown). Thus these data suggest that targeting FAK in triple-negative breast cancer patients is usually a promising approach. It is important to note that FAK has many binding partners and integrates multiple oncogenic survival pathways and sequesters tumor-suppressor pathways [1 22 Therefore future therapeutics should involve multiple targets cross-linked with FAK survival ...
Immunofluorescence studies with protein phosphatase-1 (PP1) isoforms-specific antibodies detected PP1δ, but not α or γ1, at focal adhesions. PP1δ also co-immunoprecipitated with the focal adhesion kinase (FAK) and the αv-integrin. In the present study glutathione S-transferase (GST)-PP1δ pulled-down FAK from fibroblasts extract and the interaction domain localized between residues 159 and 295 of δ. The association was confirmed by the ability to GST-FAK-related non-kinase (FRNK) to pull-down PP1δ from fibroblasts extract. GST-FRNK also pulled-down purified muscle PP1 catalytic subunit, thus indicating direct interaction between FAK and PP1. FAK displays consensus sequences for phosphorylation by cell division cycle kinase-2-cyclin B, and might be a PP1 substrate. In fact, FAK immunoprecipitated from metabolically-labelled mitotic HeLa cells without tyrosine phosphatase inhibitors was phosphorylated on Ser only and was dephosphorylated in vitro by purified muscle PP1, with loss of ...
Focal adhesion kinase (FAK) acts as an adaptor at the focal contacts serving as a junction between the extracellular matrix and actin cytoskeleton. Actin dynamics is known as a determinant step in insulin secretion. Additionally, FAK has been shown to regulate insulin signaling. To investigate the essential physiological role of FAK in pancreatic β-cells in vivo, we generated a transgenic mouse model using rat insulin promoter (RIP)-driven Cre-loxP recombination system to specifically delete FAK in pancreatic β-cells. These RIPcre+fakfl/fl mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell viability and proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with attenuated insulin/Akt (also known as protein kinase B) and extracellular signal-related kinase 1/2 signaling and increased caspase 3 activation. FAK-deficient β-cells exhibited impaired insulin secretion with normal glucose sensing and preserved Ca2+ ...
Fak is rapidly activated and triggers the assembly of a multicomponent signaling complex that has been considered to occupy a central position in the transduction and coordination of the earlier responses of cardiac myocytes to mechanical stress. In the present study, we showed comprehensive data on Fak tyrosine phosphorylation, subcellular distribution, and interaction with C-terminal region of myosin heavy chain, providing insight on the mechanism of its activation by mechanical forces in cardiac myocytes.. By using phosphospecific antibodies against tyrosine residues of Fak and Src, we extended previous demonstration of Fak/Src signaling complex activation by mechanical stress, to show the load-induced phosphorylation of specific Fak tyrosine residues Tyr397, 576/7, 861, and 925 in the rat myocardium. These results agree with a proposed model for Fak activation triggered by autophosphorylation at Tyr397 followed by the engagement of Src, which phosphorylates additional Fak tyrosine ...
TY - JOUR. T1 - Stretch-induced cell proliferation is mediated by FAK-MAPK pathway. AU - Wang, Ju Guang. AU - Miyazu, Motoi. AU - Xiang, Peng. AU - Li, Shu Nong. AU - Sokabe, Masahiro. AU - Naruse, Keiji. PY - 2005/4/29. Y1 - 2005/4/29. N2 - Previously we reported that a uni-axial cyclic stretch treatment of rat 3Y1 fibroblasts induced focal adhesion kinase (FAK) tyrosine phosphorylation followed by mitogen-activated protein kinase (MAPK) activation (Wang et al., 2001) [Wang, J.G., Miyazu, M., Matsushita, E., Sokabe, M., Naruse, K., 2001. Uni-axial cyclic stretch induces focal adhesion kinase (FAK) tyrosine phosphorylation followed by mitogen-activated protein kinase (MAPK) activation. Biochem. Biophys. Res. Comm. 288, 356-361]. In the present study, we investigated whether stretch-induced MAPK activation leads to proliferation of fibroblasts. 3Y1 fibroblasts were subjected to a uni-axial cyclic stretch treatment (1 Hz, 120% in length) and the bromodeoxyuridine (BrdU) incorporation was measured ...
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GTPase regulator associated with the focal adhesion kinase (GRAF), a putative tumor suppressor gene, is found inactivated in hematopoietic malignancies by either genetic or epigenetic abnormalities. However, the expression level of GRAF gene has not yet been studied in leukemia. The aim of this study was to investigate the expression level of GRAF gene in those patients with myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML). The expression levels of GRAF transcript were determined in 94 patients using real-time quantitative PCR (RQ-PCR). Clinical and laboratory data of these patients were collected and analyzed. The significantly decreased level of GRAF transcript was observed in three myeloid malignancies compared to controls. Within AML, there was no difference in the level of GRAF transcript among different FAB subtypes (P | 0.05). Difference was not observed in the amount of GRAF mRNA between CML at chronic phase and
This study is a Phase I dose escalation study in subjects with solid tumors. Part 1 will identify the maximum tolerated dose (MTD) using a dose-escalation procedure. Following identification of the MTD, enrollment into Parts 2, 3, 4, and 5 may be concurrent. Part 2 will explore further the safety, PK, tolerability, and anti-tumor activity of GSK2256098 in subjects with tumors known to overexpress focal adhesion kinase (FAK). Part 3 will characterize the range of biologically effective doses by assessing pharmacodynamic (PD) markers in hair, skin and tumor tissue at doses that will not go lower than 80 mg or above the MTD dose levels tested during the Phase 1 dose escalation. Part 4 will explore further the safety, PK, tolerability and anti-tumor activity of GSK2256098 in subjects with relapsed glioblastoma multiforme (GBM). The primary objective of this study is to determine the safety, tolerability, and MTD of GSK2256098. Secondary objectives are to characterize the pharmacokinetics (PK) of ...
Role of integrins and focal adhesion kinase in the orientation of dermal fibroblasts exposed to cyclic strain.: Stretch is applied to skin under normal physiolo
TY - JOUR. T1 - Promotion of skeletal muscle differentiation by K252a with tyrosine phosphorylation of focal adhesion. T2 - A possible involvement of small GTPase Rho. AU - Lee, Kun Ho. AU - Lee, Seung Hye. AU - Kim, Daegun. AU - Rhee, Sangmyung. AU - Kim, Chungho. AU - Chung, Chin Ha. AU - Kwon, Hyockman. AU - Kang, Man Sik. PY - 1999/11/1. Y1 - 1999/11/1. N2 - K252a, a protein kinase inhibitor, acts as a neurotrophic factor in several neuronal cells. In this study we show that K252a enhanced the differentiation of C2C12 myoblasts as well as tyrosine phosphorylation of several focal adhesion-associated proteins including p130(Cas), focal adhesion kinase, and paxillin. The tyrosine phosphorylation of these proteins, reaching a maximum at 30 min after K252a treatment, closely correlated with the colocalization of these proteins in focal adhesion complexes and the coimmunoprecipitation of these proteins with p130(Cas). In addition, K252a stimulated longitudinal development of stress fiber-like ...
Title:Focal Adhesion Kinase in Ovarian Cancer: A Potential Therapeutic Target for Platinum and Taxane-Resistant Tumors. VOLUME: 19 ISSUE: 3. Author(s):Arkene Levy*, Khalid Alhazzani, Priya Dondapati, Ali Alaseem, Khadijah Cheema, Keerthi Thallapureddy, Paramjot Kaur, Saad Alobid and Appu Rathinavelu. Affiliation:College of Medical Sciences, Nova Southeastern University, Fort Lauderdale, FL, Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, Rumbaugh Goodwin ...
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In this report, we provide several lines of evidence that p130Cas is a downstream mediator of FAK-promoted cell migration. First, a mutation of P712/715A in FAK abolished its ability to promote CHO cell migration (Fig. 3). The proline-rich region on FAK spanning amino acids 712-718 has been mapped as the primary binding site for p130Cas through its SH3 domain (Polte and Hanks, 1995; Harte et al., 1996), although a second proline-rich region (amino acids 875-884) can also mediate FAK binding to p130Cas (Harte et al., 1996; Polte and Hanks, 1997). In vivo coimmunoprecipitation experiments showed that FAK/ p130Cas association was reduced but not abolished by the P712/715A mutation (Fig. 6), indicating that the second proline-rich region on FAK may mediate some binding to p130Cas, as demonstrated previously (Harte et al., 1996; Polte and Hanks, 1997). However, binding of p130Cas to an alternative site clearly does not allow for FAK-promoted migration. It has also been suggested that p130Cas may ...
Advanced stages of epithelial carcinogenesis are linked to loss of intercellular adhesion, but it remains unclear how alterations in cell‐cell and cell‐matrix adhesions are coordinated to promote the early stages of cancer development. To address this, we used 3D tissue models that mimic human premalignant disease, and studied the impact of E‐cadherin suppression in early stage, epithelial tumor cells (HaCaT‐II‐4) on the expression and activity of Focal Adhesion Kinase (FAK) and Src kinase and on tumor cell motility and invasiveness. Suppression of E‐cadherin function triggered elevated expression of FAK, increased tyrosine phosphorylation of FAK and Src, and redirected these protein tyrosine kinases to a perinuclear distribution. Pharmacological inhibition of FAK or Src, by either Tyrphostin AG1007 or PP2, reduced their phosphorylation, and reversibly inhibited tumor cell motility in 2D, monolayer cultures. Decreased FAK or Src expression by lentivirus‐mediated shRNA restored ...
Cancer Therapeutics CRC Pty Ltd is developing small molecule focal adhesion kinase (FAK) inhibitors for the treatment of metastatic cancers. Focal adhesion
Introduction Weve shown previously that overexpression of constitutively dynamic Akt or activation of Akt due to constitutively dynamic Ras or individual epidermal development aspect receptor-2 (HER2) confers in breast cancers cells level of resistance to chemotherapy or radiotherapy. on phosphoinositide 3-kinase (PI3-K). An elevated baseline degree of Akt was within MCF7 cells treated with ionizing rays also. The cellular replies to doxorubicin-induced Akt phosphorylation had been potentiated following the appearance of Akt upstream activators including HER2, HER3 and focal adhesion kinase. Bottom line Used as well as our latest released outcomes displaying that constitutive Akt mediates level of resistance to radiotherapy or chemotherapy, our 443776-49-6 IC50 443776-49-6 IC50 present data claim that the doxorubicin-induced phosphorylation and activation of Akt might reveal a cellular protective mechanism of tumor cells to get over doxorubicin-induced cytotoxic results, which further works ...
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Ms. Kelsey Murrell was mentored by Dr. Richard Price and graduate co-mentor Josh Meisner(BME). Kelseys research goal was to determine the role of the signaling enzyme Focal Adhesion Kinase in macrophages, which are agents of the immune system that play a critical role in the expansion of existing blood vessels when blood flow through normal circulatory channels is blocked. Her work could lead to better understanding and treatment of peripheral artery disease ...
A decreased apoptotic response toward noxious stress is an issuing characteristic of the aging phenotype. Hydrogen peroxide or staurosporine induced apoptosis readily in young cells but not in senescent cells. We showed that focal adhesion kinase (FAK) expression and its phosphorylation at Tyr397, autophosphorylation site for focal adhesion formation, and Tyr577, Src-dependent phosphorylation site, were both increased in senescent cells. Moreover, FAK was inactivated proteolytically by apoptotic stimuli in young cells, but not in senescent cells. In addition, senescent cells whose FAK expression was downregulated by siRNA showed the increased level of apoptosis by staurosporine treatment via caspase-3 activation but not by hydrogen peroxide treatment. Interestingly dephosphorylation at Tyr577 of FAK by PP2 treatment, Src-family kinase inhibitor, induced the apoptosis by staurosporine in senescent cells but dephosphorylation at Tyr397 by downregulation of caveolin-1 was not affected. These data ...
Background: Deletion in liver cancer gene (DLC1) and phosphorylated focal adhesion kinase (p-FAK) have recently been reported as metastasis-related genes. However, the roles and prognostic values of their expression in epithelial ovarian carcinomas (EOCs) remain unclear. Methods: The expression and prognostic value of DLC1 and p-FAK Y397 in EOC were evaluated by immunohistochemistry and multivariate analysis. Results: Low expression of DLC1 and high expression of p-FAK Y397 were found in the 76 cases of EOC. The expression of DLC1 and p-FAK Y397 were negatively correlated. Multivariate analysis showed that the combination of them was an independent prognostic marker of EOC (P = 0.0319). Conclusions: DLC1 and pFAK Y397 had an association with the clinicopathologic characteristics of EOC. Expression of neither of these genes was a prognostic factor alone, but the combination revealed a significant prognostic value in the 60 cases of advanced stage EOC.
OxLDL drives NF-κB activation and VCAM-1 expression through integrin-α5β1-dependent FAK signaling; however, the mechanisms regulating FAK-dependent NF-κB signaling have remained elusive (Yurdagul et al., 2014). Here, we define a new signaling pathway involving FAK-dependent activation of the RSK pathway to promote NF-κB activation through its classic upstream mediator IKKβ. Although both RSK and NF-κB activation are known to be redox sensitive, we show that preventing integrin signaling or FAK activation does not significantly affect oxLDL-induced ROS levels, suggesting that FAK-dependent activation of the RSK-IKKβ-NK-κB pathway operates independently from oxidative stress (Abe et al., 2000; Kabe et al., 2005). Instead, oxLDL drives FAK-dependent ERK activation that results in RSK-dependent signaling to IKKβ and NF-κB. We further demonstrate elevated FAK activation in the endothelium overlying both mouse and human atherosclerotic plaques, and show that transgenic mice containing an ...
Focal adhesion kinase (FAK) is an important mediator of extracellular matrix-integrin mechano-signal transduction that regulates cell motility, survival, and proliferation. As such, FAK is being investigated as a potential therapeutic target for malignant and fibrotic diseases, and numerous clinical trials of FAK inhibitors are underway. The function of FAK in nonmalignant, nonmotile epithelial cells is not well understood. We previously showed that hepatocytes demonstrated activated FAK near stiff collagen tracts in fibrotic livers. In this study, we examined the role of liver epithelial FAK by inducing fibrotic liver disease in mice with liver epithelial FAK deficiency. We found that mice that lacked FAK in liver epithelial cells developed more severe liver injury and worse fibrosis as compared with controls. Increased fibrosis in liver epithelial FAK-deficient mice was linked to the activation of several profibrotic pathways, including the hedgehog/smoothened pathway. FAK-deficient ...
The intracellular protein tyrosine kinase FAK (focal adhesion kinase) was originally identified gy its high level of tyrosine phosphorylation in v-src-transformed cells. FAK is also highly phosphorylated during early development. In cultured cells it is localized to focal adhesion contacts and becom …
Colon cancer cells show increased resistance to chemotherapeutic agents compared to breast cancer cells (28, 29), and the molecular mechanisms of this resistance are not fully known. While colon cancer cells express high levels of Src family kinases (30), the survival signal pathways associated with its expression are not known (31). In the present study, we have demonstrated that colon cancer cell lines have survival signals operative through both FAK and Src activities, suggesting that the combination of these signals may contribute to their resistance to apoptosis. Furthermore, these results have shown for the first time that combined dual Src and FAK inhibition is effective for inducing apoptosis in colon cancer cell lines.. Several studies have demonstrated up-regulation of FAK expression in colorectal cancer (11, 13, 14, 24, 25, 32), and it appears that colon cells up-regulate expression of FAK at early stages of tumorigenesis, even before carcinoma has been detected (11). Our previous ...
To decipher how cells crawl, researchers have knocked out a key signaling protein known as focal adhesion kinase (FAK), which relays messages from the cell surface. But the results of these knockout studies have been confused by the fact that a FAK paralogue gets up-regulated in these cells. Lim et al. now clear up the picture.. As a cell crawls along a surface, it temporarily attaches at sites called focal adhesions. FAK concentrates at focal adhesions and passes on signals from integrins that have latched onto molecules in the extracellular matrix. Fibroblasts missing FAK remain rounded up instead of flattening out on a surface and crawl sluggishly. Both of which might be expected if focal adhesions are impaired. However, FAK-lacking cells actually have an inordinate number of focal adhesions and have increased RhoA activity-a factor that spurs focal adhesion and stress fiber formation, thus promoting the rounded shape by increasing the internal contractile force.. Lim et al. now show that ...
To date, the targeting of FAK has faced significant challenges in the clinic. Early studies in ovarian cancer cell lines and xenografts demonstrated that knockdown of FAK expression enhanced docetaxel efficacy in docetaxel-sensitive and docetaxel-resistant models in vitro and in vivo (31, 32). Subsequently, TAE226, a TKI that targets FAK and IGF-1R, was demonstrated to enhance docetaxel cytotoxicity (33); however, at this point, development stalled due to the drug failing clinical trials. Other first-generation FAK TKIs had problems with compensatory upregulation of the FAK homolog, Pyk2, which affected clinical efficacy (34). Newer FAK TKIs targeting FAK and Pyk2, PF-00562271, and its second-generation PF-04554878, were well tolerated in phase I clinical trials (35, 36), and the latter is currently in phase Ib and II clinical trials (37). While the efficacy of combining PF-00562271 with cytotoxic agents has not been reported, coadministration of this TKI with sunitinib in a hepatocellular ...
PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to each other and their surroundings) and spreading processes (how cells move around). It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility. This gene encodes a cytosolic protein tyrosine kinase that is found concentrated in the focal adhesions that form among cells attaching to extracellular matrix constituents. The encoded protein is a member of the FAK subfamily of protein tyrosine kinases that included PYK2, but lacks significant sequence similarity to kinases from other subfamilies. It also includes a large FERM domain. With the exception of certain types of blood cells, most cells express FAK. FAK tyrosine kinase activity can be activated, which plays a key important early step in cell ...
Western blot analysis. Whole cell lysate for SDS-PAGE and Western blot analysis for FAK expression was prepared as previously reported ( 24). To prepare lysate from dissected in vivo tumors, samples were snap frozen in liquid nitrogen immediately after sacrificing the animals and stored at −80°C. The lysate was incubated on ice in radioimmunoprecipitation assay buffer for 2 h before being homogenized using a mortar and pestle. The homogenized sample was centrifuged, and the supernatant was collected and stored at −80°C. Protein quantification and Western blot for FAK were done as previously reported ( 24). Equal loading was confirmed with β-actin (0.1 μg/mL, Sigma Chemical). Densitometric analysis was done using the Scion Imaging software (Scion Corporation), using total FAK or actin as a control for each sample.. Cytotoxicity assay. The IC50 was determined as described previously ( 23). Briefly, 2,000 cells per well were seeded onto 96-well plates and allowed to adhere overnight, after ...
Interrupting the interplay between cancer cells and extracellular matrix (ECM) is a strategy to halt tumor progression and stromal invasion. Perlecan/heparan sulfate proteoglycan 2 (HSPG2) is an extracellular proteoglycan that orchestrates tumor angiogenesis, proliferation, differentiation and invasion. Metastatic prostate cancer (PCa) cells degrade perlecan-rich tissue borders to reach bone, including the basement membrane, vasculature, reactive stromal matrix and bone marrow. Domain IV-3, perlecans last 7 immunoglobulin repeats, mimics native proteoglycan by promoting tumoroid formation. This is reversed by matrilysin/matrix metalloproteinase-7 (MMP-7) cleavage to favor cell dispersion and tumoroid dyscohesion. Both perlecan and Domain IV-3 induced a strong focal adhesion kinase (FAK) dephosphorylation/deactivation. MMP-7 cleavage of perlecan reversed this, with FAK in dispersed tumoroids becoming phosphorylated/activated with metastatic phenotype. We demonstrated Domain IV-3 interacts with ...
The metastatic lymph node 64 (MLN64) gene was initially identified as highly expressed in the metastatic lymph node from breast cancer. It is localized in q12-q21 of the human chromosome 17 and is often co-amplified with erbB-2. However, the role played by MLN64 in breast cancer remains unclear. In the present study, the expression of MLN64 was examined in a breast cancer cohort using quantitative real-time PCR and immunohistochemical staining. It demonstrated that MLN64 was highly expressed in breast tumours compared to corresponding background tissues at both transcript level and protein level. The elevated level of MLN64 transcripts was correlated with the poor prognosis and overall survival of the patients. A panel of breast cancer cell sublines was subsequently developed by knockdown of MLN64 expression. Loss of MLN64 expression in MCF-7 cells resulted in a significant reduction of cell growth (absorbance for MCF-7ΔMLN64 being 0.87±0.07, ...
NSCLC remains a significant clinical challenge due to the fact that few medical treatments are effective in this disease. It is well known that NSCLC displays either primary or acquired resistance to chemotherapy and targeted therapy. The limitations of current therapies are evident in mutant KRAS NSCLC. For instance, direct inhibitors of oncogenic KRAS lack the specificity needed for their deployment in vivo (47-49). Furthermore, inhibition of the canonical KRAS signaling pathways MEK1/2, PI3K, and mTORC1/2 have not shown benefits in lung cancer patients that justify their FDA approval for clinical use (4). As a consequence, there has been an intense interest in the identification of novel therapeutic targets for mutant KRAS NSCLC.. The data presented in this article lead to several important conclusions: not only is FAK a targetable vulnerability of mutant KRAS lung cancer, but its inhibition also leads to significant radiosensitizing effects that can be exploited in a combination therapy ...
PF 431396 is a dual focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2) inhibitor (IC50 values are 2 and 11 nM respectively).
The findings are published in this weeks online issue of The Journal of Cell Biology. Blood vessels are tightly lined with endothelial cells, which form a permeability barrier to circulating cells and molecules. "Our studies show that pharmacological or genetic inhibition of the endothelial protein focal adhesion kinase, or FAK, prevents tumor spread by enhancing the vessel barrier function." The researchers found that selective FAK inhibition within endothelial cells prevented spontaneous tumor metastasis without alterations in tumor size. Schlaepfer, with colleagues at the UC San Diego Moores Cancer Center, is exploring whether inhibiting targets like FAK, which has important regulatory functions in both tumor cells and blood vessels, might provide a dual mechanism for preventing both cancer growth and spread. Using mouse models of breast, ovarian and melanoma tumors, first author Christine Jean, PhD, showed that FAK activity was elevated in the blood vessels surrounding tumors, compared to ...
Crystal Structures of the FAK Kinase in Complex with TAE226 and Related Bis-Anilino Pyrimidine Inhibitors Reveal a Helical DFG Conformation. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, ...
A multiple-functionalized targeting delivery system was prepared by self-assembly for efficient delivery of Cas9/sgRNA plasmids to targeted tumor cell nuclei. The Cas9/sgRNA plasmids were compacted by protamine in the presence of calcium ions to form nanosized cores, which were further decorated by peptide and aptamer conjugated alginate derivatives. With the help of the nuclear location signal peptide and AS1411 aptamer with specific affinity for nucleolin in the tumor cell membrane and nuclei, the delivery vector can specifically deliver the plasmid to the nuclei of tumorous cells for knocking out the protein tyrosine kinase 2 (PTK2) gene to down-regulate focal adhesion kinase (FAK). The tumor cell apoptosis induced by genome editing is mitochondrial-dependent. In addition, FAK knockout results in negative regulation on the PI3K/AKT signaling pathway. Meanwhile, favorable modulation on various proteins involved in tumor progression can be realized by genome editing. The enhanced E-cadherin and ...
mRNAs localize to specific regions within neurons, where they can be translated to quickly generate large amounts of a protein in the place where it is needed. Due to the large size of neurons, this is much more efficient than translating all mRNAs in a single place and then shipping out each protein to its site of action. But the movement and translation of these mRNAs must be tightly regulated, potentially by extracellular signals such as growth factors.. Tsai et al. discovered that EGF boosts expression of the κ-opioid receptor (KOR) by stimulating both the nuclear export and translation of KOR mRNA. The key to this dual control was an RNA-binding protein called Grb7. EGF prods a phosphatase called SHP-2 to dephosphorylate Grb7 in the nucleus, prompting it to bind KOR mRNA and recruit a protein complex involved in nuclear export. But EGF also stimulated focal adhesion kinase to rephosphorylate Grb7 in the cytoplasm, causing it to release the mRNA for translation into KOR protein.. Senior ...
Z3330795 (talk) 16:14, 11 April 2013 (EST)FAK-Focal Adhesion Kinase Antibody --Z3376548 (talk) 16:15, 11 April 2013 (EST) Catenin beta Antibody (6F9) --Z3374087 (talk) 16:15, 11 April 2013 (EST)alpha-2-catenin --Z3331321 (talk) 16:16, 11 April 2013 (EST) Anti-α-E-Catenin Rabbit ...
Z3330795 (talk) 16:14, 11 April 2013 (EST)FAK-Focal Adhesion Kinase Antibody --Z3376548 (talk) 16:15, 11 April 2013 (EST) Catenin beta Antibody (6F9) --Z3374087 (talk) 16:15, 11 April 2013 (EST)alpha-2-catenin --Z3331321 (talk) 16:16, 11 April 2013 (EST) Anti-α-E-Catenin Rabbit ...
FAK兔多克隆抗体(ab55335)可与小鼠, 大鼠, 人样本反应并经WB, ELISA, IHC实验严格验证,被1篇文献引用。所有产品均提供质保服务,中国75%以上现货。
FAK兔多克隆抗体(ab4794)可与人样本反应并经WB实验严格验证,被4篇文献引用。中国75%以上现货,所有产品均提供质保服务,可通过电话、电邮或微信获得本地专属技术支持。
Lung cancer is the most common cancer and also the leading cause of cancer-related death worldwide among both men and women. Small cell lung cancer (SCLC) accounts for 15% of all cases. It is the most aggressive one in its clinical behavior with a 5-year overall survival as low as 5%. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase which regulates integrin and growth factor signaling pathways involved in cell proliferation, survival, migration, and invasion. FAK is overexpressed and/or activated in many cancers including SCLC. We hypothesized that FAK may represent a good target for therapeutic interventions in SCLC and tested the changes of cell phenotype induced by a FAK inhibitor (PF-228). ...
The objectives of this research were to better characterize the protein signaling complexes that form in response to spermatozoa binding to the bovine oocyte vitelline membrane and to elucidate their potential involvement in oocyte activation. Integrins located on the vitelline membrane of bovine oocytes have been implicated in mediating the sperm-oocyte interaction. Anti-integrin function blocking antibodies and immunofluorescence were utilized in order to reveal that the αV and β1 integrin subunits are essential for fertilization in the bovine and could form the integrin heterodimer involved in the sperm-oocyte interaction. Focal adhesion kinase is localized to focal adhesions and is a key component of signal transduction pathways mediated by integrins. The presence of focal adhesion kinase in bovine oocytes was verified by real-time polymerase chain reaction and immunoprecipitation and the localization of focal adhesion kinase at the site of sperm binding to the oocyte plasma membrane was verified
Turnover of focal adhesions allows cell retraction, which is essential for cell migration. The mammalian spectraplakin protein, ACF7 (Actin-Crosslinking Factor 7), promotes focal adhesion dynamics by targeting of microtubule plus ends towards focal adhesions. However, it remains unclear how the activity of ACF7 is regulated spatiotemporally to achieve focal adhesion-specific guidance of microtubule. To explore the potential mechanisms, we resolve the crystal structure of ACF7s NT (amino-terminal) domain, which mediates F-actin interactions. Structural analysis leads to identification of a key tyrosine residue at the calponin homology (CH) domain of ACF7, whose phosphorylation by Src/FAK (focal adhesion kinase) complex is essential for F-actin binding of ACF7. Using skin epidermis as a model system, we further demonstrate that the phosphorylation of ACF7 plays an indispensable role in focal adhesion dynamics and epidermal migration in vitro and in vivo. Altogether, our findings provide critical ...
In the present study we first elucidated the NTN‐1-mediated signaling pathway in BBB protection following SAH in rats. Our results showed that endogenous NTN‐1 and DCC receptor were upregulated in the early stage after SAH. Exogenous NTN‐1 treatment reduced brain edema and BBB permeability and thereby alleviated neurological deficits after SAH, which were accompanied by an increase in FAK phosphorylation and a decrease in RhoA activity as well as endothelial junction protein upregulation. In contrast, silencing of endogenous NTN‐1 by special siRNA exacerbated brain edema, BBB disruption, and neurological deficits. Furthermore, knockdown DCC using DCC siRNA or inhibition of FAK by Fib‐14 abolished the neuroprotective effects of exogenous NTN‐1 on BBB integrity and brain edema formation, which were associated with the increased RhoA activity and MMP‐9 and the degraded endothelial junction proteins and basal lamina at 24 hours after SAH. Taken together, these findings support our ...
A recently developed stable isotope dilution liquid chromatography-multiple reaction/mass spectrometry method to quantify focal adhesion kinase (FAK) activation loop phosphorylation was used to study endogenous Src kinase activity. This revealed that bis-phosphorylated pTyr576/Tyr577-FAK was a biomarker of Src activity and inactivation in vitro and in cell culture. Mouse embryonic fibroblasts (MEFs) expressing endogenous Src family kinases contained 65% unmodified Tyr576/Tyr577, 33% mono-phosphorylated-pTyr576-FAK, and 6% bis-phosphorylated-pTyr576/pTyr577-FAK. In contrast, MEFs expressing oncogenic Y529FSrc contained 38% unmodified Tyr576/Tyr577-FAK, 29% mono-phosphorylated-pTyr576-FAK, and 19% bis-phosphorylated-pTyr576/pTyr577-FAK. This new method has made it possible to accurately determine the absolute amounts of FAK phosphorylation that occur after Src inhibition in cell culture and in vitro with increasing concentrations of the Src inhibitor ...
Mitogen-induced changes in the actin cytoskeleton are accompanied by changes in the tyrosine phosphorylation of several proteins in focal adhesions. In this study, we have investigated the role of RAFTK (also termed Pyk2/CAK-β), a cytoplasmic tyrosine kinase related to focal adhesion kinase (FAK), in heregulin-mediated signal transduction in breast cancer cells. Stimulation of T47D cells with heregulin (HRG) induced the tyrosine phosphorylation of RAFTK and the formation of a multiprotein complex. Maximal phosphorylation of the proteins participating in this complex occurred within 2 h of HRG stimulation. Analyses of the members of the HRG-stimulated complex revealed that RAFTK associated with p190 RhoGAP (p190), RasGAP, c-Abl as well as with the focal adhesion molecules p130cas and paxillin. c-Abl was found to be associated with RAFTK through the region of RAFTK containing amino acids 419-1009. Site-directed mutagenesis of Y881 aa within the RAFTK sequence abolished the binding of RAFTK to ...
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that controls cell proliferation and survival downstream of integrin-matrix receptors. However, under deprivation of anchorage, FAK translocates to the nucleus. The nucleolus, a non-membrane structure within the nucleus, is important in the control of ribosome biogenesis, regulates the sequestration of nuclear proteins, and increased nucleolar size is a marker of aggressive tumors. Nucleostemin, a nucleolar-localized protein, acts to modulate cell cycle progression and anchorage-independent cell growth. Although many drugs have low efficacy on tumor cells cultured in suspension, nanomolar small molecule FAK inhibitor (PF-271 or PND-1186) addition can prevent anchorage-independent growth of tumor cells as spheroids through mechanism(s) that remain unresolved. Here, we show that pharmacological FAK inhibitor (FAK-I) treatment or kinase-dead (KD) FAK re-expression analyses reduced breast cancer (MDA-MB-231 and 4T1-L) anchorage-independent ...
Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the ...