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Swapan K Dasgupta, Anhquyen Le, K Vinod Vijayan, Perumal Thiagarajan
Treatment with dasatinib, a tyrosine kinase inhibitor, is associated with edema, pleural effusion, and pulmonary edema. We investigated the effect of dasatinib on the barrier function of human microvascular endothelial cells-1 (HMEC-1) in vitro and in vivo. The permeability of HMEC-1 to fluorescein isothiocyante (FITC)-dextran increased in Transwell chambers within 5 min following the addition of therapeutic concentrations of dasatinib. The change in permeability was associated with increased activation of RhoA GTPase and its effector Rho-associated coiled-coil kinase 1(ROCK1)...
March 18, 2017: Cancer Medicine
Peta M Bradbury, Kylie Turner, Camilla Mitchell, Kaitlyn R Griffin, Shiloh Middlemiss, Loretta Lau, Rebecca Dagg, Elena Taran, Justin Cooper-White, Ben Fabry, Geraldine M O'Neill
The Cas family of focal adhesion proteins contain a highly conserved C-terminal focal adhesion targeting (FAT) domain. To determine the role of the FAT domain we compared wildtype exogenous NEDD9 with a hybrid construct in which the NEDD9 FAT domain is exchanged for the p130Cas FAT domain. Fluorescence recovery after photobleaching (FRAP) revealed significantly slowed exchange of the fusion protein at focal adhesions and significantly slower 2D migration. No differences were detected in cell stiffness measured with Atomic Force Microscopy (AFM) and cell adhesion forces measured with a magnetic tweezer device...
February 21, 2017: Journal of Cell Science
Ian M Evans, Susan A Kennedy, Ketevan Paliashvili, Tapesh Santra, Maiko Yamaji, Ruth C Lovering, Gary Britton, Paul Frankel, Walter Kolch, Ian C Zachary
p130Cas is a polyvalent adapter protein essential for cardiovascular development, and with a key role in cell movement. In order to identify the pathways by which p130Cas exerts its biological functions in endothelial cells we mapped the p130Cas interactome and its dynamic changes in response to VEGF using high-resolution mass spectrometry and reconstruction of protein interaction (PPI) networks with the aid of multiple PPI databases. VEGF enriched the p130Cas interactome in proteins involved in actin cytoskeletal dynamics and cell movement, including actin-binding proteins, small GTPases and regulators or binders of GTPases...
February 2017: Molecular & Cellular Proteomics: MCP
Yasuhiro Sawada, Hiroaki Hirata
It is 10 years since we reported Cas as a cell mechano-sensor that converts stretching force to a biochemical signal. While we have been looking into the mechanism of how Cas molecules are extended, it appears that the source of stretching force does not derive from actomyosin contraction, but originates from actin polymerization. Furthermore, we have found that phosphorylated Cas links actomyosin contraction to cell migration by tensin 1-mediated association with inwardly moving actin filaments. Collectively, Cas serves as a force sensor at the cell leading edges as well as a part of force transmission machinery, i...
2016: Clinical Calcium
Binod Kumar, Bala Chandran
Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically associated with human endothelial cell hyperplastic Kaposi's sarcoma and B-cell primary effusion lymphoma. KSHV infection of adherent endothelial and fibroblast cells are used as in vitro models for infection and KSHV enters these cells by host membrane bleb and actin mediated macropinocytosis or clathrin endocytosis pathways, respectively. Infection in endothelial and fibroblast cells is initiated by the interactions between multiple viral envelope glycoproteins and cell surface associated heparan sulfate (HS), integrins (α3β1, αVβ3 and αVβ5), and EphA2 receptor tyrosine kinase (EphA2R)...
November 14, 2016: Viruses
Binod Kumar, Dipanjan Dutta, Jawed Iqbal, Mairaj Ahmed Ansari, Arunava Roy, Leela Chikoti, Gina Pisano, Mohanan Valiya Veettil, Bala Chandran
Kaposi's sarcoma-associated herpesvirus (KSHV) binding to the endothelial cell surface heparan sulfate is followed by sequential interactions with α3β1, αVβ3 and αVβ5 integrins and Ephrin A2 receptor tyrosine kinase (EphA2R). These interactions activate host cell pre-existing FAK, Src, PI3-K and RhoGTPase signaling cascades, c-Cbl mediated ubiquitination of receptors, recruitment of CIB1, p130Cas and Crk adaptor molecules, and membrane bleb formation leading to lipid raft dependent macropinocytosis of KSHV into human microvascular dermal endothelial (HMVEC-d) cells...
October 2016: PLoS Pathogens
Mayumi Takeya, Yuushi Okumura, Takeshi Nikawa
Skin can respond to various types of internal and/or external mechanostimuli, such as excessive tension caused by body growth or decompression due to weight loss, which significantly affect skin morphology. Mechanosensors, including p130Cas, are reported to play a role in deformation and subsequent recovery of various tissues including skeletal muscles and blood vessels. However, the role of mechanotransduction via p130Cas in the regulation of skin size remains unclear. In this report, p130Cas activation was manipulated using a fibroblast-embedded collagen gel model or mouse skin contraction model...
October 7, 2016: Journal of Physiological Sciences: JPS
Maria Elisa Perico, Silvia Grasso, Matteo Brunelli, Guido Martignoni, Enrico Munari, Enrico Moiso, Giulio Fracasso, Tiziana Cestari, Hassan Y Naim, Vincenzo Bronte, Marco Colombatti, Dunia Ramarli
The expression of Prostate Specific-Membrane Antigen (PSMA) increases in high-grade prostate carcinoma envisaging a role in growth and progression. We show here that clustering PSMA at LNCaP or PC3-PSMA cell membrane activates AKT and MAPK pathways thus promoting proliferation and survival. PSMA activity was dependent on the assembly of a macromolecular complex including filamin A, beta1 integrin, p130CAS, c-Src and EGFR. Within this complex beta1 integrin became activated thereby inducing a c-Src-dependent EGFR phosphorylation at Y1086 and Y1173 EGF-independent residues...
October 3, 2016: Oncotarget
S R Frank, C P Köllmann, J F van Lidth de Jeude, J R Thiagarajah, L H Engelholm, M Frödin, S H Hansen
DOCK proteins are guanine nucleotide exchange factors for Rac and Cdc42 GTPases. DOCK1 is the founding member of the family and acts downstream of integrins via the canonical Crk-p130Cas complex to activate Rac GTPases in numerous contexts. In contrast, DOCK5, which possesses the greatest similarity to DOCK1, remains sparingly studied. Here we establish that DOCK5 has a non-redundant role in regulating motile and invasive capacities of epithelial cells. DOCK1 is constitutively associated with sites of integrin attachment termed focal adhesions (FAs)...
September 26, 2016: Oncogene
Vered Horwitz, Ben Davidson, Dganit Stern, Claes G Tropé, Tali Tavor Re'em, Reuven Reich
OBJECTIVE: Ezrin and p130Cas are structural proteins with an important role in signaling pathways and have been shown to promote cancer dissemination. We previously reported on overexpression of both ezrin and p130Cas in breast carcinoma effusions compared to primary carcinomas. Since ovarian and breast carcinomas share the ability to disseminate by forming malignant effusions, we sought to study the role of these molecules in ovarian carcinoma (OC). METHODS: OC cell lines were cultured in two different 3-dimensional conditions, on alginate scaffolds and as spheroids, which served as models for solid tumor and malignant effusions, respectively...
2016: PloS One
Guilong Zhang, Lukui Chen, Kouhong Sun, Ahsan Ali Khan, Jianghua Yan, Hongyi Liu, Ailin Lu, Ning Gu
Glioma occurs due to multi-gene abnormalities. Neuropilin-1 (NRP-1), as a transmembrane protein, involves in glioma proliferation, invasion, and migration, as well as tumor angiogenesis. The cytoplasmic protein, GAIP/RGS19-interacting protein (GIPC1), could regulate the clathrin-vesicles trafficking and recycling. Here, we show that NRP-1 co-localizes and co-immunoprecipitates with GIPC1, and the C-terminal SEA-COOH motif of NRP-1 interacts specially with the named from three proteins: PSD-95 (a 95 kDa protein involved in signaling at the post-synaptic density), DLG (the Drosophila melanogaster Discs Large protein) and ZO-1 (the zonula occludens 1 protein involved in maintenance of epithelial polarity) (PDZ) domain of GIPC1 in glioma cells...
October 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Jia Li, Ruping Wang, Dale D Tang
BACKGROUND: The intermediate filament protein vimentin undergoes reversible phosphorylation and dephosphorylation at Ser-56, which plays an important role in regulating the contraction-relaxation cycles of smooth muscle. The protein phosphatases that mediate vimentin dephosphorylation in smooth muscle have not been previously investigated. METHODS: The associations of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) with vimentin in mouse tracheal rings was evaluated by co-immunoprecipitation...
2016: Respiratory Research
Yiqing Zhao, Anthony Scott, Peng Zhang, Yujun Hao, Xiujing Feng, Saigopal Somasundaram, Ahmad M Khalil, Joseph Willis, Zhenghe Wang
Protein tyrosine phosphatase receptor T (PTPRT) is frequently mutated in a variety of human cancers including colorectal cancer. Here we report that PTPRT knockout increases the size of mouse colon tumors in the Apcmin+/- genetic background, suggesting that inactivation of PTPRT promotes tumor progression. We previously demonstrated that PTPRT dephosphorylates paxillin at tyrosine-Y88 residue. Consistently, phosphorylation of Y88 paxillin (pY88) is up-regulated in colon tumors derived from Apcmin+/- Ptprt-/- mice...
July 18, 2016: Oncotarget
Antonina Frolov, Ian M Evans, Ningning Li, Kastytis Sidlauskas, Ketevan Paliashvili, Nicola Lockwood, Angela Barrett, Sebastian Brandner, Ian C Zachary, Paul Frankel
Imatinib was the first targeted tyrosine kinase inhibitor to be approved for clinical use, and remains first-line therapy for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia. We show that treatment of human glioblastoma multiforme (GBM) tumour cells with imatinib and the closely-related drug, nilotinib, strikingly increases tyrosine phosphorylation of p130Cas, focal adhesion kinase (FAK) and the downstream adaptor protein paxillin (PXN), resulting in enhanced cell migration and invasion...
2016: Scientific Reports
Monica E Burgett, Justin D Lathia, Patrick Roth, Amy S Nowacki, Deni S Galileo, Elena Pugacheva, Ping Huang, Amit Vasanji, Meizhang Li, Tatiana Byzova, Tom Mikkelsen, Shideng Bao, Jeremy N Rich, Michael Weller, Candece L Gladson
The secretion of soluble pro-angiogenic factors by tumor cells and stromal cells in the perivascular niche promotes the aggressive angiogenesis that is typical of glioblastoma (GBM). Here, we show that angiogenesis also can be promoted by a direct interaction between brain tumor cells, including tumor cells with cancer stem-like properties (CSCs), and endothelial cells (ECs). As shown in vitro, this direct interaction is mediated by binding of integrin αvβ3 expressed on ECs to the RGD-peptide in L1CAM expressed on CSCs...
July 12, 2016: Oncotarget
Anna A Birukova, Alok S Shah, Yufeng Tian, Grzegorz Gawlak, Nicolene Sarich, Konstantin G Birukov
Increased vascular endothelial cell (EC) permeability is a result of intercellular gap formation that may be induced by contraction-dependent and contraction-independent mechanisms. This study investigated a role of the adaptor protein vinculin in EC permeability induced by contractile (thrombin) and noncontractile (IL-6) agonists. Although thrombin and IL-6 caused a similar permeability increase in human pulmonary ECs and disrupted the association between vinculin and vascular endothelial-cadherin, they induced different patterns of focal adhesion (FA) arrangement...
October 2016: American Journal of Respiratory Cell and Molecular Biology
P Dourlen, F J Fernandez-Gomez, C Dupont, B Grenier-Boley, C Bellenguez, H Obriot, R Caillierez, Y Sottejeau, J Chapuis, A Bretteville, F Abdelfettah, C Delay, N Malmanche, H Soininen, M Hiltunen, M-C Galas, P Amouyel, N Sergeant, L Buée, J-C Lambert, B Dermaut
A recent genome-wide association meta-analysis for Alzheimer's disease (AD) identified 19 risk loci (in addition to APOE) in which the functional genes are unknown. Using Drosophila, we screened 296 constructs targeting orthologs of 54 candidate risk genes within these loci for their ability to modify Tau neurotoxicity by quantifying the size of >6000 eyes. Besides Drosophila Amph (ortholog of BIN1), which we previously implicated in Tau pathology, we identified p130CAS (CASS4), Eph (EPHA1), Fak (PTK2B) and Rab3-GEF (MADD) as Tau toxicity modulators...
April 26, 2016: Molecular Psychiatry
Yusuke Makino, Kazunori Hamamura, Yoshifumi Takei, Robiul Hasan Bhuiyan, Yuki Ohkawa, Yuhsuke Ohmi, Hideyuki Nakashima, Keiko Furukawa, Koichi Furukawa
We previously demonstrated that focal adhesion kinase (FAK), p130Cas and paxillin are crucially involved in the enhanced malignant properties under expression of ganglioside GD3 in melanoma cells. Therefore, molecules existing in the GD3-mediated signaling pathway could be considered as suitable targets for therapeutic intervention in malignant melanoma. The aim of this study was to determine whether blockade of p130Cas and/or paxillin by RNAi suppresses melanoma growth. We found a suitable dose (40 μM siRNA, 25 μl/tumor) of the siRNA to suppress p130Cas in the xenografts generated in nu/nu mice...
August 2016: Biochimica et Biophysica Acta
Yuan Wang, Feng Yan, Qing Ye, Xiao Wu, Fan Jiang
Promoting endothelial cell (EC) migration is important not only for therapeutic angiogenesis, but also for accelerating re-endothelialization after vessel injury. Several recent studies have shown that inhibition of protein tyrosine phosphatase 1B (PTP1B) may promote EC migration and angiogenesis by enhancing the vascular endothelial growth factor receptor-2 (VEGFR2) signalling. In the present study, we demonstrated that PTP1B inhibitor could promote EC adhesion, spreading and migration, which were abolished by the inhibitor of Rac1 but not RhoA GTPase...
April 7, 2016: Scientific Reports
Tae-Sun Ha, Hye-Young Park, Su-Bin Seong, Hee-Yul Ahn
Angiotensin II (Ang II) induces the pathological process of vascular structures, including renal glomeruli by hemodynamic and nonhemodynamic direct effects. In kidneys, Ang II plays an important role in the development of proteinuria by the modification of podocyte molecules. We have previously found that Ang II suppressed podocyte AMP-activated protein kinase (AMPK) via Ang II type 1 receptor and MAPK signaling pathway. In the present study, we investigated the roles of AMPK on the changes of p130Cas of podocyte by Ang II...
April 2016: Journal of Korean Medical Science
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