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Focal adhesion kinase

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https://www.readbyqxmd.com/read/28915654/daurinol-blocks-breast-and-lung-cancer-metastasis-and-development-by-inhibition-of-focal-adhesion-kinase-fak
#1
Jong Kyu Woo, Hyun Jin Jung, Ji-Youn Park, Ju-Hee Kang, Byung Il Lee, DongYun Shin, Chu Won Nho, Soo-Young Cho, Je Kyung Seong, Seung Hyun Oh
FAK overexpression has been reported in diverse primary and metastatic tumor tissues, supporting its pro-tumorigenic and pro-metastatic roles. Therefore, we have developed a neo-treatment strategy using daurinol to effectively treat cancer metastasis. Daurinol blocked cancer cell migration and invasion in vitro and exhibited anti-metastatic activity in an experimental metastasis model of breast and lung cancer. Daurinol selectively inhibited phosphorylation of FAK at Tyr925, Tyr576/577, and Tyr397 sites in a dose- and time-dependent manner...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28912461/vimentin-knockout-results-in-increased-expression-of-sub-endothelial-basement-membrane-components-and-carotid-stiffness-in-mice
#2
Benoit Langlois, Ekaterina Belozertseva, Ara Parlakian, Mustapha Bourhim, Jacqueline Gao-Li, Jocelyne Blanc, Lei Tian, Dario Coletti, Carlos Labat, Zhor Ramdame-Cherif, Pascal Challande, Véronique Regnault, Patrick Lacolley, Li Zhenlin
Intermediate filaments are involved in stress-related cell mechanical properties and in plasticity via the regulation of focal adhesions (FAs) and the actomyosin network. We investigated whether vimentin regulates endothelial cells (ECs) and vascular smooth muscle cells (SMCs) and thereby influences vasomotor tone and arterial stiffness. Vimentin knockout mice (Vim(-/-)) exhibited increased expression of laminin, fibronectin, perlecan, collagen IV and VE-cadherin as well as von Willebrand factor deposition in the subendothelial basement membrane...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28903319/loss-of-giant-obscurins-alters-breast-epithelial-cell-mechanosensing-of-matrix-stiffness
#3
Kimberly M Stroka, Bin Sheng Wong, Marey Shriver, Jude M Phillip, Denis Wirtz, Aikaterini Kontrogianni-Konstantopoulos, Konstantinos Konstantopoulos
Obscurins are a family of RhoGEF-containing proteins with tumor and metastasis suppressing roles in breast epithelium. Downregulation of giant obscurins in normal breast epithelial cells leads to reduced levels of active RhoA and of its downstream effectors. Herein, we elucidate how depletion of giant obscurins affects the response of breast epithelial cells to changes in the mechanical properties of the microenvironment. We find that knockdown of obscurins increases cell morphodynamics, migration speed, and diffusivity on polyacrylamide gels of ≥ 1 kPa, presumably by decreasing focal adhesion area and density as well as cell traction forces...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28882999/mir-193b-regulated-signaling-networks-serve-as-tumor-suppressors-in-liposarcoma-and-promote-adipogenesis-in-adipose-derived-stem-cells
#4
Ying Z Mazzu, Yulan Hu, Rajesh K Soni, Kelly M Mojica, Li-Xuan Qin, Phaedra Agius, Zachary M Waxman, Aleksandra Mihailovic, Nicholas D Socci, Ronald C Hendrickson, Thomas Tuschl, Samuel Singer
Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo. Deep RNA sequencing on 93 WDLS, 145 DDLS and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared to normal fat. Re-introduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC)...
September 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/28881682/inhibition-of-fak-kinase-activity-preferentially-targets-cancer-stem-cells
#5
Vihren N Kolev, Winnie F Tam, Quentin G Wright, Sean P McDermott, Christian M Vidal, Irina M Shapiro, Qunli Xu, Max S Wicha, Jonathan A Pachter, David T Weaver
Because cancer stem cells (CSCs) have been implicated in chemo-resistance, metastasis and tumor recurrence, therapeutic targeting of CSCs holds promise to address these clinical challenges to cancer treatment. VS-4718 and VS-6063 are potent inhibitors of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates cell signals transmitted by integrins and growth factor receptors. We report here that inhibition of FAK kinase activity by VS-4718 or VS-6063 preferentially targets CSCs, as demonstrated by a panel of orthogonal CSC assays in cell line models and surgically resected primary breast tumor specimens cultured ex vivo...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28880199/the-role-of-focal-adhesion-kinase-in-keratinocyte-fibrogenic-gene-expression
#6
Michael Januszyk, Sun Hyung Kwon, Victor W Wong, Jagannath Padmanabhan, Zeshaan N Maan, Alexander J Whittam, Melanie R Major, Geoffrey C Gurtner
Abnormal skin scarring causes functional impairment, psychological stress, and high socioeconomic cost. Evidence shows that altered mechanotransduction pathways have been linked to both inflammation and fibrosis, and that focal adhesion kinase (FAK) is a key mediator of these processes. We investigated the importance of keratinocyte FAK at the single cell level in key fibrogenic pathways critical for scar formation. Keratinocytes were isolated from wildtype and keratinocyte-specific FAK-deleted mice, cultured, and sorted into single cells...
September 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28877984/%C3%AE-5%C3%AE-1-integrinpromotes-tension-dependent-mammary-epithelial-cell-invasion-by-engaging-the-fibronectin-synergy-site
#7
Y A Miroshnikova, G I Rozenberg, L Cassereau, M Pickup, J K Mouw, G Ou, K L Templeman, I Elloumi-Hannachi, K Gooch, A L Sarang-Sieminski, A J García, V M Weaver
Tumors are fibrotic and characterized by abundant, remodeled and cross-linked collagen that stiffens the extracellular matrix stroma. The stiffened collagenous stroma fosters malignant transformation of the tissue by increasing tumor cell tension to promote focal adhesion formation and potentiate growth factor receptor signaling through ERK and PI3 kinase. Importantly, collagen cross-linking requires fibronectin. Fibrotic tumors contain abundant fibronectin and tumor cells frequently up regulate the fibronectin receptor α5β1 integrin...
September 6, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28877491/%C3%AE-1-integrin-mediated-adhesion-is-lipid-bilayer-dependent
#8
Seoyoung Son, George J Moroney, Peter J Butler
Integrin-mediated adhesion is a central feature of cellular adhesion, locomotion, and endothelial cell mechanobiology. Although integrins are known to be transmembrane proteins, little is known about the role of membrane biophysics and dynamics in integrin adhesion. We treated human aortic endothelial cells with exogenous amphiphiles, shown previously in model membranes, and computationally, to affect bilayer thickness and lipid phase separation, and subsequently measured single-integrin-molecule adhesion kinetics using an optical trap, and diffusion using fluorescence correlation spectroscopy...
September 5, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28871113/trib3-inhibits-proliferation-and-promotes-osteogenesis-in-hbmscs-by-regulating-the-erk1-2-signaling-pathway
#9
Cui Zhang, Fan-Fan Hong, Cui-Cui Wang, Liang Li, Jian-Ling Chen, Fei Liu, Ren-Fu Quan, Jin-Fu Wang
Osteogenic differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs) is regulated by various factors, including bone morphogenetic proteins (BMPs), Notch, growth hormones and mitogen-activated protein kinases (MAPKs). Tribbles homolog 3 (TRIB3), a pseudokinase, plays an important role in cancer cells and adipocytes. However, TRIB3 function in osteogenic differentiation is unknown, although it is involved in regulating signaling pathways associated with osteogenic differentiation. Here, we found that TRIB3 was highly expressed during osteogenic differentiation in hBMSCs...
September 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28869459/modulation-of-the-mesenchymal-stem-cell-migration-capacity-via-preconditioning-with-topographic-microstructure
#10
Zhengdong Li, Xun Xu, Weiwei Wang, Karl Kratz, Xianlei Sun, Jie Zou, Zijun Deng, Friedrich Jung, Manfred Gossen, Nan Ma, Andreas Lendlein
Controlling mesenchymal stem cells (MSCs) behavior is necessary to fully exploit their therapeutic potential. Various approaches are employed to effectively influence the migration capacity of MSCs. Here, topographic microstructures with different microscale roughness were created on polystyrene (PS) culture vessel surfaces as a feasible physical preconditioning strategy to modulate MSC migration. By analyzing trajectories of cells migrating after reseeding, we demonstrated that mobilization velocity of human adipose derived mesenchymal stem cells (hADSCs) could be promoted and persisted by brief preconditioning with the appropriate microtopography...
August 28, 2017: Clinical Hemorheology and Microcirculation
https://www.readbyqxmd.com/read/28867754/sushi-repeat-containing-protein-x-linked-2-promotes-angiogenesis-through-the-urokinase-type-plasminogen-activator-receptor-dependent-integrin-%C3%AE-v%C3%AE-3-focal-adhesion-kinase-pathways
#11
Kuiliang Liu, Jianghao Fan, Jing Wu
Sushi repeat-containing protein X-linked 2 (SRPX2) is a newly identified chondroitin sulfate proteoglycan that is markedly elevated in multiple solid tumors. It is also suggested that SRPX2 is associated with angiogenesis. A conditioned medium of SRPX2 overexpressing colorectal cancer (CRC) cells and SRPX2 recombinant protein was used to evaluate the effect of secretory SRPX2 on the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) and the involved molecular mechanisms. It was revealed that the activity of SRPX2 is dependent on the urokinase-type plasminogen activator receptor and cooperation of the integrin αvβ3 co-receptor...
2017: Drug Discoveries & Therapeutics
https://www.readbyqxmd.com/read/28860193/structure-functional-insights-into-the-interaction-between-the-cas-family-scaffolding-protein-p130cas-and-the-focal-adhesion-associated-protein-paxillin
#12
Chi Zhang, Darcie J Miller, Cristina D Guibao, Dominique M Donato, Steven K Hanks, Jie J Zheng
The CAs family scaffolding 130Cas is a Src substrate localized in focal adhesions (FAs) and functions in integrin signaling to promote cell motility, invasion, proliferation, and survival. P130Cas targeting to FAs is essential for its tyrosine phosphorylation and downstream signaling. Although the N-terminal SH3 domain is important for p130Cas localization, it has also been reported that the C-terminal region is involved in p130Cas FA targeting. The Cterminal region of p130Cas or Cas family homology domain (CCHD), has been reported to adopt a structure similar to that of the focal adhesion kinase (FAK) C-terminal focal adhesion targeting (FAT) domain...
August 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28857467/impaired-erythropoietin-synthesis-in-chronic-kidney-disease-is-caused-by-alterations-in-extracellular-matrix-composition
#13
Gemma Olmos, José M Muñoz-Félix, Inés Mora, Anton Gerhard Müller, Maria Piedad Ruiz-Torres, José M López-Novoa, Diego Rodríguez-Puyol
Renal fibrosis and anaemia are two of the most relevant events in chronic kidney disease. Fibrosis is characterized by the accumulation of extracellular matrix proteins in the glomeruli and tubular interstitium. Anaemia is the consequence of a decrease in erythropoietin production in fibrotic kidneys. This work analyses the possibility that the accumulation of abnormal collagens in kidney interstitium could be one of the mechanisms responsible for erythropoietin decreased synthesis. In renal interstitial fibroblast grown on collagen I, erythropoietin mRNA expression and HIF-2α protein decreased, whereas focal adhesion kinase protein (FAK) phosphorylation and proteasome activity increased, compared to cells grown on collagen IV...
August 30, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28852378/rack1-regulates-neural-development
#14
REVIEW
Leah Kershner, Kristy Welshhans
Receptor for activated C kinase 1 (RACK1) is an evolutionarily conserved scaffolding protein within the tryptophan-aspartate (WD) repeat family of proteins. RACK1 can bind multiple signaling molecules concurrently, as well as stabilize and anchor proteins. RACK1 also plays an important role at focal adhesions, where it acts to regulate cell migration. In addition, RACK1 is a ribosomal binding protein and thus, regulates translation. Despite these numerous functions, little is known about how RACK1 regulates nervous system development...
July 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28852375/schwann-cell-development-maturation-and-regeneration-a-focus-on-classic-and-emerging-intracellular-signaling-pathways
#15
REVIEW
Luca Franco Castelnovo, Veronica Bonalume, Simona Melfi, Marinella Ballabio, Deborah Colleoni, Valerio Magnaghi
The development, maturation and regeneration of Schwann cells (SCs), the main glial cells of the peripheral nervous system, require the coordinate and complementary interaction among several factors, signals and intracellular pathways. These regulatory molecules consist of integrins, neuregulins, growth factors, hormones, neurotransmitters, as well as entire intracellular pathways including protein-kinase A, C, Akt, Erk/MAPK, Hippo, mTOR, etc. For instance, Hippo pathway is overall involved in proliferation, apoptosis, regeneration and organ size control, being crucial in cancer proliferation process...
July 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28846700/pfak-y397-overexpression-as-both-a-prognostic-and-a-predictive-biomarker-for-patients-with-metastatic-osteosarcoma
#16
Kamolrat Thanapprapasr, Adisak Nartthanarung, Duangmani Thanapprapasr, Artit Jinawath
Focal adhesion kinase (FAK) is important for tumor cell survival and metastasis in various cancers. However, its expression and prognostic value in patients with metastatic osteosarcoma remain unknown. We investigated the expression of FAK and its phosphorylated form (pFAK-Y397) in osteosarcoma tissues from 53 patients by immunohistochemistry and evaluated their correlations with clinicopathologic characteristics and outcomes. The prognostic values were assessed using Kaplan-Meier survival and Cox regression analyses...
2017: PloS One
https://www.readbyqxmd.com/read/28846105/c-reactive-protein-binds-to-integrin-%C3%AE-2-and-fc%C3%AE-receptor-i-leading-to-breast-cell-adhesion-and-breast-cancer-progression
#17
E-S Kim, S Y Kim, M Koh, H-M Lee, K Kim, J Jung, H S Kim, W K Moon, S Hwang, A Moon
C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin α2 signaling...
August 28, 2017: Oncogene
https://www.readbyqxmd.com/read/28842658/src-mediated-tyrosine-phosphorylation-of-protein-kinase-d2-at-focal-adhesions-regulates-cell-adhesion
#18
Nisha Durand, Ligia I Bastea, Heike Döppler, Tim Eiseler, Peter Storz
Dependent on their cellular localization, Protein Kinase D (PKD) enzymes regulate different processes including Golgi transport, cell signaling and response to oxidative stress. The localization of PKD within cells is mediated by interaction with different lipid or protein binding partners. With the example of PKD2, we here show that phosphorylation events can also contribute to localization of subcellular pools of this kinase. Specifically, in the present study, we show that tyrosine phosphorylation of PKD2 at residue Y87 defines its localization to the focal adhesions and leads to activation...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28834752/clathrin-independent-endocytosis-suppresses-cancer-cell-blebbing-and-invasion
#19
Mikkel Roland Holst, Maite Vidal-Quadras, Elin Larsson, Jie Song, Madlen Hubert, Jeanette Blomberg, Magnus Lundborg, Maréne Landström, Richard Lundmark
Cellular blebbing, caused by local alterations in cell-surface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrin-independent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension-mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM...
August 22, 2017: Cell Reports
https://www.readbyqxmd.com/read/28832962/rubiarbonone-c-inhibits-platelet-derived-growth-factor-induced-proliferation-and-migration-of-vascular-smooth-muscle-cells-through-the-fak-map-kinase-and-stat3-tyr-705-signaling-pathways
#20
Hyun-Soo Park, Khong Trong Quan, Joo-Hui Han, Sang-Hyuk Jung, Do-Hyung Lee, Eunji Jo, Tae-Wan Lim, Kyung-Sun Heo, Min Kyun Na, Chang-Seon Myung
BACKGROUND AND PURPOSE: The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF) are important steps in cardiovascular diseases, including neointimal lesion formation, myocardial infarction, and atherosclerosis. Here, we evaluated the rubiarbonone C-mediated signaling pathways that regulate PDGF-induced VSMC proliferation and migration. EXPERIMENTAL APPROACH: Cell proliferation and migration were measured in cells treated with rubiarbonone C followed by PDGF-BB treatment using the MTT assay, [(3) H]-thymidine incorporation, flow cytometry, and wound healing migration assay, matrix metalloproteinase (MMP) gelatin zymography, a fluorescence assay for F-actin...
August 18, 2017: British Journal of Pharmacology
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