Anti-angiogenic therapy inhibits tumor growth and is considered as a potential clinical therapy for malignant glioma. However, inevitable recurrences and unexpected tumor resistance, particularly increased invasion ability of glioma cell, were observed after anti-angiogenic treatment. The underlying mechanism remains undetermined. Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are closely associated with cell migration; therefore, we investigated the possible role of these kinases in rat C6 glioma cell invasion induced by bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor (VEGF). The effects of bevacizumab on migration and invasion of C6 glioma cells were investigated in vitro and in vivo. The cells proliferation, migration, and invasion were determined by MTT assay, wound healing, and transwell assay, respectively. Invasive potential of glioma cells in vivo was assessed by counting vimentin-positive cells crossing the solid tumor rim by
Suppressor of cytokine signaling (SOCS) proteins serve as negative regulators of cytokine receptor signaling. However, SOCS proteins are not only induced via the JAK/STAT pathway, but are also transcribed on triggering of pattern recognition receptors such as TLRs. We now show that SOCS1 can also be induced by the non-TLR pattern recognition receptor Dectin-1 in murine bone marrow-derived dendritic cells and macrophages (BMMs). The C-type lectin Dectin-1 binds to yeasts and signals either in an autonomous manner or can be triggered in combination with TLRs. In our study, SOCS1 was expressed independently of any TLR engagement as a direct target gene of the Dectin-1 ligand Zymosan. Induction of SOCS1 was mediated by a novel pathway encompassing the tyrosine kinases Src and Syk that activated the downstream kinase proline-rich tyrosine kinase 2. Proline-rich tyrosine kinase 2, in turn, caused activation of the MAPK ERK, thereby triggering SOCS1 induction. SOCS1 did not modulate Dectin-1 signaling ...
The product encoded by this gene is preferentially expressed in hematopoietic cells and belongs to the paxillin protein family. Similar to other members of this focal-adhesion-associated adaptor-protein family, it has four leucine-rich LD-motifs in the N-terminus and four LIM domains in the C-terminus. It may function in cell type-specific signaling by associating with PYK2, a member of focal adhesion kinase family. As a substrate for a tyrosine kinase in lymphoid cells, this protein may also function in, and be regulated by, tyrosine kinase activity. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Jan 2009 ...
The current series of experiments used 2 different vascular tissues to confirm that endothelial NO production increased as dietary salt intake increased; the mechanism of this increase has now been clarified. Recent observations from this laboratory demonstrated a dose-dependent effect of salt intake on activation of endothelial Pyk2, which recruited and activated c-Src.21 Novel findings of the present study include the observation that dietary salt intake induced an intracellular signaling complex that not only contained Pyk2 and c-Src but also p85 and p110α; this complex was directly involved in the activation of Akt that, in turn, produced the posttranslational modification that increased NOS3 production of NO in the setting of a high-salt diet. By adding to the elegant studies of Matsui et al,37 who showed that Pyk2 is involved in modulating NOS3 activity in angiogenesis and ischemia, the data further supported an integral role for Pyk2 in signal transduction events that regulate NOS3 ...
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).
Recognition by CD8,sup,+,/sup, cytotoxic T lymphocytes (CTLs) of antigenic peptides bound to major histocompatibility class (MHC) I molecules on target cells leads to sustained calcium mobilization and CTL degranulation resulting in perforin-dependent killing. We report that beta,sub,1,/sub, and beta,sub,3,/sub, integrin-mediated adhesion to extracellular matrix proteins on target cells and/or surfaces dramatically promotes CTL degranulation. CTLs, when adhered to fibronectin but not CTL in suspension, efficiently degranulate upon exposure to soluble MHC.peptide complexes, even monomeric ones. This adhesion induces recruitment and activation of the focal adhesion kinase Pyk2, the cytoskeleton linker paxillin, and the Src kinases Lck and Fyn in the contact site. The T cell receptor, by association with Pyk2, becomes part of this adhesion-induced activation cluster, which greatly increases its signaling ...
The erbB-2 type I tyrosine kinase receptor is involved in cell differentiation, proliferation, migration and carcinogenesis, although its precise biological functions remain unclear. Heregulin (HRG) can activate ErbB-2 receptors as a result of ErbB-2/ErbB-3 or ErbB-2/ErbB-4 heterodimeric interactions. HRG can induce either a growth arrest or a mitogenic response, and may be associated with regulation of cytoskeleton reorganization and cell migration. Mitogen-induced changes in the actin cytoskeleton are accompanied by changes in the tyrosine phosphorylation of several focal adhesion proteins. The gene encoding a novel human cytoplasmic tyrosine kinase termed RAFTK, which is related to focal adhesion kinase (FAK), has been cloned and the product subsequently shown to interact with different protein tyrosine kinases such as Src, as well as focal adhesion molecules such as paxillin and HAF1. ...
We report the results of a national quality-control survey on glycohemoglobin GHb, monitored in France by the Soci t Fran aise de Biologie Clinique on behalf of the authority of the Agence du Medicament. A sample of lyophilized hemolysate was sent to 3109 laboratories. Results were obtained from 2770 laboratories. HbA1c, HbA1, and total GHb...
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 ...
SAP90/PSD-95-associated protein 2 (SAPAP2, also known as DLGAP2) is a member of a protein family whose members specifically interact with PSD-95/SAP90, a membrane-associated guanylate kinase localized at postsynaptic density (PSD) in neuronal cells. Like the other SAPAP proteins, SAPAP2 is thought to be an adaptor protein that also interacts with different synaptic scaffolding proteins, cytoskeletal and signaling components, such as focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). SAPAP2 mRNA is targeted to cell bodies in a similar manner to SAPAP1 and -4, whereas SAPAP3 mRNA is detected mainly in cell bodies. At least three isoforms of SAPAP2 are known to exist. This SAPAP2 antibody will not cross-react with other SAPAP proteins. ...
This study demonstrates an important role for the nonreceptor tyrosine kinase Pyk2 in the integrin-mediated activation of PMNs that contributes to normal degranulation responses required for efficient host defense to S. aureus infection. Pyk2-deficient PMNs exhibited reduced degranulation responses following integrin ligation both in vitro and during bacterial infection in vivo; however, they responded normally to soluble agonists, suggesting that the integrin signaling pathway was the major response affected in the pyk2 mutant cells. It is clear that unlike Src-family or Syk tyrosine kinases, Pyk2 is acting in a more distal step in the integrin signaling pathway, because many integrin-mediated functions were normal in pyk2−/− PMNs, including attachment, adhesion, and integrin-mediated activation of superoxide production. These limited impairments correlate with the only partially reduced integrin-mediated tyrosine phosphorylation responses, although reduction in phosphorylation of specific ...
Leupaxin is an understudied 43-kDa protein that was originally reported as having a lymphoid-restricted expression pattern.16 We show for the first time that leupaxin is also highly expressed in aorta and in cultured SMCs. In addition, our studies reveal that leupaxin can undergo cytoplasmic/nuclear shuttling and functions as an SRF cofactor in the nucleus. We found that leupaxin forms a complex with SRF, associates with CArG-containing regions of the SMC-specific promoters, and that ectopic expression of leupaxin induces SMC differentiation marker gene expression. Subsequent studies indicated that enhanced FAK activity attenuates the nuclear accumulation of leupaxin and limits the ability of leupaxin to enhance SRF-dependent gene transcription. Thus, these studies indicate that sequestration of leupaxin to focal adhesion plaques may be 1 mechanism by which extracellular matrix-dependent signals might regulate phenotypic switching of SMCs.. Leupaxin belongs to a family of proteins including ...
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
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In this study, we investigated the role of intercellular adhesion molecule-2 (ICAM2) in the testis. ICAM2 is a cell adhesion protein having important roles in cell migration, especially during inflammation when leukocytes cross the endothelium. Herein, we showed ICAM2 to be expressed by germ and Sertoli cells in the rat testis. When a monospecific antibody was used for immunolocalization experiments, ICAM2 was found to surround the heads of elongating/elongated spermatids in all stages of the seminiferous epithelial cycle. To determine whether ICAM2 is a constituent of apical ectoplasmic specialization (ES), co-immunoprecipitation and dual immunofluorescence staining were performed. Interestingly, ICAM2 was found to associate with β1-integrin, nectin-3, afadin, Src, proline-rich tyrosine kinase 2, annexin II, and actin. Following CdCl_2 treatment, ICAM2 was found to be upregulated during restructuring of the seminiferous epithelium, with round spermatids becoming increasingly immunoreactive for ...
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 ...
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.
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 ...
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 ...
Reagents for the antigen ABL1 / c-abl oncogene 1, non-receptor tyrosine kinase (pTyr469) stained with biotin in the Antibody Database
Academic Dissertations;Academic Dissertations--South Carolina;Focal Adhesion Protein-Tyrosine Kinases;Mitogens;Focal Adhesion Kinase 1;Phospholipase D;Cell ...