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1دورية أكاديمية
المؤلفون: Jokl, Elliot, Mullan, Aoibheann F, Simpson, Kara, Birchall, Lindsay, Pearmain, Laurence, Martin, Katherine, Pritchett, James, Raza, Sayyid, Shah, Rajesh, Hodson, Nigel W, Williams, Craig J, Camacho, Elizabeth, Zeef, Leo, Donaldson, Ian, Athwal, Varinder S, Hanley, Neil A, Piper Hanley, Karen
المصدر: Jokl , E , Mullan , A F , Simpson , K , Birchall , L , Pearmain , L , Martin , K , Pritchett , J , Raza , S , Shah , R , Hodson , N W , Williams , C J , Camacho , E , Zeef , L , Donaldson , I , Athwal , V S , Hanley , N A & Piper Hanley , K 2023 , ' PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis ' , Cell Reports , vol. 42 , no. 11 , 113414 ....
مصطلحات موضوعية: Humans, Myofibroblasts/pathology, Pulmonary Fibrosis/pathology, Cell Differentiation, Mechanotransduction, Cellular, Cicatrix/pathology, Fibrosis, Chromatin/metabolism, p21-Activated Kinases/metabolism
الوصف: Myofibroblasts are responsible for scarring during fibrosis. The scar propagates mechanical signals inducing a radical transformation in myofibroblast cell state and increasing profibrotic phenotype. Here, we show mechanical stress from progressive scarring induces nuclear softening and de-repression of heterochromatin. The parallel loss of H3K9Me3 enables a permissive state for distinct chromatin accessibility and profibrotic gene regulation. Integrating chromatin accessibility profiles with RNA expression provides insight into the transcription network underlying the switch in profibrotic myofibroblast states, emphasizing mechanoadaptive regulation of PAK1 as key drivers. Through genetic manipulation in liver and lung fibrosis, loss of PAK1-dependent signaling impairs the mechanoadaptive response in vitro and dramatically improves fibrosis in vivo. Moreover, we provide human validation for mechanisms underpinning PAK1-mediated mechanotransduction in liver and lung fibrosis. Collectively, these observations provide insight into the nuclear mechanics driving the profibrotic chromatin landscape in fibrosis, highlighting actomyosin-dependent mechanisms as potential therapeutic targets in fibrosis.
الإتاحة: https://doi.org/10.1016/j.celrep.2023.113414Test
https://research.manchester.ac.uk/en/publications/a24d5c48-f33f-4099-87b6-8e7832d2013aTest
http://www.scopus.com/inward/record.url?scp=85176921518&partnerID=8YFLogxKTest
https://www.mendeley.com/catalogue/559916c3-d100-387d-9ef4-22196d1d8169Test/ -
2دورية أكاديمية
المساهمون: College of Medicine, Dept. of Obstetrics & Gynecology, Sung Hoon Kim, SiHyun Cho, Hyo Jin Ihm, Young Sang Oh, Seung-Ho Heo, Sail Chun, Hosub Im, Hee Dong Chae, Chung-Hoon Kim, Byung Moon Kang, Cho, Si Hyun
مصطلحات موضوعية: Animals, Case-Control Studies, Cells, Cultured, Diethylhexyl Phthalate/toxicity, Endometriosis/chemically induced, Endometriosis/epidemiology, Female, Humans, MAP Kinase Signaling System, Matrix Metalloproteinase 2/metabolism, Matrix Metalloproteinase 9/metabolism, Mice, Inbred NOD, SCID, Phthalic Acids/urine, Plasticizers/toxicity, Prospective Studies, Stromal Cells/metabolism, p21-Activated Kinases/genetics, p21-Activated Kinases/metabolism
الوصف: CONTEXT: Although phthalates were shown to have several negative effects on reproductive function in animals, its role in the pathogenesis of endometriosis remains to be elucidated. OBJECTIVE: We aimed to investigate the in vitro and in vivo effects of di-(2-ethylhexyl)-phthalate (DEHP) and to compare the urinary levels of several phthalate metabolites between women with and without endometriosis. DESIGN: For experimental studies, we used endometrial cell culture and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models. We also performed a prospective case-control study for human sample analyses. SETTING: The study was conducted at an academic center. MAIN OUTCOME MEASURES: The activities of matrix metalloproteinase (MMP)-2 and 9, cellular invasiveness, phosphorylation of extracellular signal-regulated kinase (Erk), and expression of p21-activated kinase 4 were analyzed in endometrial cells treated with DEHP. The implant size was compared between NOD/SCID mice fed with and without DEHP. Urinary concentrations of several phthalate metabolites were compared between women with and without endometriosis. RESULTS: In vitro treatment of endometrial cells with DEHP led to significant increases of MMP-2 and 9 activities, cellular invasiveness, Erk phosphorylation, and p21-activated kinase 4 expression. The size of the endometrial implant was significantly larger in the NOD/SCID mice fed with DEHP compared with those fed with vehicle. The urinary concentration of mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate, and mono (2-ethyl-5-carboxyphentyl) phthalate were significantly higher in women with endometriosis compared with controls. CONCLUSION: These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells. ; open
العلاقة: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; J01318; OAK-2015-06276; https://ir.ymlib.yonsei.ac.kr/handle/22282913/156936Test; T201504947; JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol.100(12) : E1502-E1511, 2015
الإتاحة: https://doi.org/10.1210/jc.2015-2478Test
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156936Test -
3دورية أكاديمية
المؤلفون: Shin, Yong Jae, Kim, Eun Hye, Roy, Adhiraj, Kim, Jeong-Ho
المصدر: Biochemistry and Molecular Medicine Faculty Publications
مصطلحات موضوعية: cdc42 GTP-Binding Protein--metabolism, p21-Activated Kinases--metabolism, rac GTP-Binding Proteins--metabolism, Biochemistry, Biophysics, and Structural Biology
الوصف: P21-activated kinase 1 (PAK1) is activated by binding to GTP-bound Rho GTPases Cdc42 and Rac via its CRIB domain. Here, we provide evidence that S79 in the CRIB domain of PAK1 is not directly involved in this binding but is crucial for PAK1 activation. S79A mutation reduces the binding affinity of PAK1 for the GTPases and inhibits autophosphorylation and kinase activity of PAK1. Thus, this mutation abrogates the ability of PAK1 to induce changes in cell morphology and motility and to promote malignant transformation of prostate epithelial cells. We also show that growth of the prostate cancer cell line PC3 is inhibited by the treatment of a PAK1-inhibiting peptide comprising 19 amino acids centered on S79, but not by the PAK1 peptide containing the S79A mutation, and that this growth inhibition is correlated with reduced autophosphorylation activity of PAK1. Together, these findings demonstrate a significant role of S79 in PAK1 activation and provide evidence for a novel mechanism of the CRIB-mediated interaction of PAK1 with Cdc42 and Rac.
وصف الملف: application/pdf
العلاقة: https://hsrc.himmelfarb.gwu.edu/smhs_biochem_facpubs/96Test; https://hsrc.himmelfarb.gwu.edu/cgi/viewcontent.cgi?article=1096&context=smhs_biochem_facpubsTest
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4دورية أكاديمية
المساهمون: Seung Hee Baek, Hae Weon Cho, Young-Chang Kwon, Ji Hyun Lee, Moon Jong Kim, Hyangkyu Lee, Kwang-Min Choe, Lee, Hyang Kyu
مصطلحات موضوعية: Actins/metabolism, Animals, Drosophila Proteins/metabolism, Drosophila melanogaster/physiology, Epidermis/pathology, Epidermis/physiology, Larva/anatomy & histology, Larva/physiology, Myosins/metabolism, Recombinant Fusion Proteins/genetics, Recombinant Fusion Proteins/metabolism, Wound Healing/physiology, p21-Activated Kinases/genetics, p21-Activated Kinases/metabolism, rac1 GTP-Binding Protein/genetics, rac1 GTP-Binding Protein/metabolism, Wound repair, Cell migration, Chemotaxis, Cell polarization, Actin cable
الوصف: Rho-family small GTPases regulate epithelial cell sheet migration by organizing actin and myosin during wound healing. Here, we report that Pak3, but not Pak1, is a downstream target protein for Rac1 in wound closure of the Drosophila larval epidermis. Pak3-deficient larvae failed to close a wound hole and this defect was not rescued by Pak1 expression, indicating differential functions of the two proteins. Pak3 localized to the wound margin, which selectively required Rac1. Pak3-deficient larvae showed severe defects in actin-myosin organization at the wound margin and in submarginal cells, which was reminiscent of the phenotypes of Rac1-deficient larvae. These results suggest that Pak3 specifically mediates Rac1 signaling in organizing actin and myosin during Drosophila epidermal wound healing. ; open
العلاقة: FEBS LETTERS; J00890; OAK-2012-00205; https://ir.ymlib.yonsei.ac.kr/handle/22282913/90291Test; http://www.sciencedirect.com/science/article/pii/S001457931200110XTest; T201200423; FEBS LETTERS, Vol.586(6) : 772-777, 2012
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5دورية أكاديمية
المؤلفون: Lee, M. Y., San Martin, Alejandra, Mehta, P. K., Dikalova, A. E., Garrido, A. M., Datla, S. R., Lyons, Erin, Krause, Karl-Heinz, Banfi, Botond, Lambeth, J. D., Lassegue, Bernard, Griendling, K. K.
المصدر: ISSN: 1079-5642 ; Arteriosclerosis, thrombosis, and vascular biology, vol. 29, no. 4 (2009) p. 480-487.
مصطلحات موضوعية: info:eu-repo/classification/ddc/616.07, Animals, Apoptosis, Carrier Proteins/metabolism, Cell Movement, Cell Proliferation, Cells, Cultured, Cofilin 2/metabolism, Collagen Type I/metabolism, Disease Models, Animal, Femoral Artery/enzymology/injuries, Fibronectins/metabolism, Hyperplasia, Mice, Inbred C57BL, Knockout, Muscle, Smooth, Vascular/ enzymology/injuries/pathology, NADH, NADPH Oxidoreductases/deficiency/genetics/ metabolism, Phosphorylation, Time Factors, Transfection, Tunica Intima/ enzymology/injuries/pathology, p21-Activated Kinases/metabolism
الوصف: OBJECTIVE: Vascular NADPH oxidases (Noxes) have been implicated in cardiovascular diseases; however, the importance of individual Nox homologues remains unclear. Here, the role of the vascular smooth muscle cell (VSMC) Nox1 in neointima formation was studied using genetically modified animal models. METHODS AND RESULTS: Wire injury-induced neointima formation in the femoral artery, along with proliferation and apoptosis, was reduced in Nox1(y/-) mice, but there was little difference in Tg(SMCnox1) mice compared with wild-type (WT) mice. Proliferation and migration were reduced in cultured Nox1(y/-) VSMCs and increased in Tg(SMCnox1) cells. Tg(SMCnox1) cells exhibited increased fibronectin secretion, but neither collagen I production nor cell adhesion was affected by alteration of Nox1. Using antibody microarray and Western blotting analysis, increased cofilin phosphorylation and mDia1 expression and decreased PAK1 expression were detected in Nox1(y/-) cells. Overexpression of S3A, a constitutively active cofilin mutant, partially recovered reduced migration of Nox1(y/-) cells, suggesting that reduction in cofilin activity contributes to impaired migration of Nox1(y/-) VSMCs. CONCLUSIONS: These results indicate that Nox1 plays a critical role in neointima formation by mediating VSMC migration, proliferation, and extracellular matrix production, and that cofilin is a major effector of Nox1-mediated migration. Inhibition of Nox1 may be an efficient strategy to suppress neointimal formation.
العلاقة: info:eu-repo/semantics/altIdentifier/pmid/19150879; https://archive-ouverte.unige.ch/unige:11001Test; unige:11001
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6دورية أكاديمية
المؤلفون: Gavillet, M., Martinod, K., Renella, R., Wagner, D.D., Williams, D.A.
المصدر: American journal of hematology, vol. 93, no. 2, pp. 269-276
مصطلحات موضوعية: Animals, Citrullination, Extracellular Traps/metabolism, Histones/metabolism, Mice, NADPH Oxidases/metabolism, Reactive Oxygen Species/metabolism, Signal Transduction, p21-Activated Kinases/metabolism, p21-Activated Kinases/physiology, rac GTP-Binding Proteins/metabolism, rac GTP-Binding Proteins/physiology
الوصف: NET formation in mice (NETosis) is supported by reactive oxygen species (ROS) production by NADPH oxidase and histone hypercitrullination by peptidylarginine deiminase 4 (PAD4). Rac1 and Rac2, expressed in polymorphonuclear neutrophils (PMNs), regulate the cytoskeleton, cell shape, adhesion, and migration and are also essential components of the NADPH oxidase complex. We aimed to explore the role of the Rac signaling pathway including the upstream guanosine exchange factor (GEF) activator, Vav, and a downstream effector, the p21-activated kinase, Pak, on NETosis in PMNs using a previously described flow-cytometry-based assay. Rac2 -/- PMNs showed reduced levels of citrullinated histone H3 (H3Cit)-positive cells and defective NETosis. Rac1 Δ/Δ ; Rac2 -/- PMNs demonstrated a further reduction in PMA-induced H3Cit levels and a more profound impairment of NETosis than deletion of Rac2 alone, suggesting an overlapping role of these two highly related proteins. Genetic knockouts of Vav1, or Vav2, did not impair H3Cit response to phorbol myristate ester (PMA) or NETosis. Combined, Vav1 and Vav3 deletions decreased H3Cit response and caused a modest but significant impairment of NETosis. Pharmacologic inhibition of Pak by two inhibitors with distinct mechanisms of action, led to reduced H3Cit levels after PMA stimulation, as well as significant inhibition of NETosis. We validated the importance of Pak using Pak2 Δ/Δ PMNs, which demonstrated significantly impaired histone H3 citrullination and NETosis. These data confirm and more comprehensively define the key role of the Rac signaling pathway in PMN NETosis. The Rac signaling cascade may represent a valuable target for inhibition of NETosis and related pathological processes.
العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29124783; info:eu-repo/semantics/altIdentifier/eissn/1096-8652; https://serval.unil.ch/notice/serval:BIB_D6331230E133Test; urn:issn:0361-8609
الإتاحة: https://doi.org/10.1002/ajh.24970Test
https://serval.unil.ch/notice/serval:BIB_D6331230E133Test -
7دورية أكاديمية
المساهمون: Pang, Xiaodong (authoraut), Zhou, Huan-Xiang (authoraut)
مصطلحات موضوعية: Binding Sites, Intrinsically Disordered Proteins/chemistry, Intrinsically Disordered Proteins/metabolism, Kinetics, Models, Molecular, Protein Binding, Wiskott-Aldrich Syndrome Protein/chemistry, Wiskott-Aldrich Syndrome Protein/metabolism, cdc42 GTP-Binding Protein/chemistry, cdc42 GTP-Binding Protein/metabolism, p21-Activated Kinases/chemistry, p21-Activated Kinases/metabolism
الوصف: Intrinsically disordered proteins (IDPs) are often involved in signaling and regulatory functions, through binding to cellular targets. Many IDPs undergo disorder-to-order transitions upon binding. Both the binding mechanisms and the magnitudes of the binding rate constants can have functional importance. Previously we have found that the coupled binding and folding of any IDP generally follows a sequential mechanism that we term dock-and-coalesce, whereby one segment of the IDP first docks to its subsite on the target surface and the remaining segments subsequently coalesce around their respective subsites. Here we applied our TransComp method within the framework of the dock-and-coalesce mechanism to dissect the binding kinetics of two Rho-family GTPases, Cdc42 and TC10, with two intrinsically disordered effectors, WASP and Pak1. TransComp calculations identified the basic regions preceding the GTPase binding domains (GBDs) of the effectors as the docking segment. For Cdc42 binding with both WASP and Pak1, the calculated docking rate constants are close to the observed overall binding rate constants, suggesting that basic-region docking is the rate-limiting step and subsequent conformational coalescence of the GBDs on the Cdc42 surface is fast. The possibility that conformational coalescence of the WASP GBD on the TC10 surface is slow warrants further experimental investigation. The account for the differences in binding rate constants among the three GTPase-effector systems and mutational effects therein yields deep physical and mechanistic insight into the binding processes. Our approach may guide the selection of mutations that lead to redesigned binding pathways. ; Keywords: Binding kinetics, Coupled binding and folding, Dock-and-coalesce mechanism, Intrinsically disordered proteins, Transient-complex theory ; Grant Number: R01 GM058187, GM0585187 ; Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840055Test.
وصف الملف: 1 online resource; computer
العلاقة: Proteins--1097-0134--1097-0134; fsu:620938; (IID) FSU_pmch_26879470; (DOI) 10.1002/prot.25018; (PMCID) PMC4840055; (RID) 26879470; (EID) 26879470; https://diginole.lib.fsu.edu/islandora/object/fsu%3A620938/datastream/TN/view/Mechanism%20and%20rate%20constants%20of%20the%20Cdc42%20GTPase%20binding%20with%20intrinsically%20disordered%20effectors.jpgTest
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8
المؤلفون: Botond Banfi, Alejandra San Martin, S. Raju Datla, Bernard Lassègue, Anna Dikalova, Erin Lyons, Abel Martin Garrido, Karl-Heinz Krause, Puja K. Mehta, Moo Yeol Lee, Kathy K. Griendling, J. David Lambeth
المصدر: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 29, No 4 (2009) pp. 480-487
مصطلحات موضوعية: Time Factors, Vascular smooth muscle, Apoptosis, Carrier Proteins/metabolism, ddc:616.07, 030204 cardiovascular system & hematology, Muscle, Smooth, Vascular, Extracellular matrix, Mice, 0302 clinical medicine, Cell Movement, NADH, NADPH Oxidoreductases, Phosphorylation, Cells, Cultured, Mice, Knockout, 0303 health sciences, NADPH Oxidase 1, Cofilin, Cell biology, Femoral Artery, Biochemistry, NOX1, cardiovascular system, Fibronectins/metabolism, Cardiology and Cardiovascular Medicine, p21-Activated Kinases/metabolism, Neointima, Cofilin 2, Formins, Collagen Type I/metabolism, Biology, Transfection, Collagen Type I, Article, 03 medical and health sciences, Animals, Genetically modified animal, Cell Proliferation, 030304 developmental biology, Hyperplasia, Femoral Artery/enzymology/injuries, NADH, NADPH Oxidoreductases/deficiency/genetics/ metabolism, Muscle, Smooth, Vascular/ enzymology/injuries/pathology, Fibronectins, Mice, Inbred C57BL, Fibronectin, Disease Models, Animal, p21-Activated Kinases, Tunica Intima/ enzymology/injuries/pathology, Cofilin 2/metabolism, biology.protein, Carrier Proteins, Tunica Intima
الوصف: Objective— Vascular NADPH oxidases (Noxes) have been implicated in cardiovascular diseases; however, the importance of individual Nox homologues remains unclear. Here, the role of the vascular smooth muscle cell (VSMC) Nox1 in neointima formation was studied using genetically modified animal models. Methods and Results— Wire injury–induced neointima formation in the femoral artery, along with proliferation and apoptosis, was reduced in Nox1 y/− mice, but there was little difference in Tg SMCnox1 mice compared with wild-type (WT) mice. Proliferation and migration were reduced in cultured Nox1 y/− VSMCs and increased in Tg SMCnox1 cells. Tg SMCnox1 cells exhibited increased fibronectin secretion, but neither collagen I production nor cell adhesion was affected by alteration of Nox1. Using antibody microarray and Western blotting analysis, increased cofilin phosphorylation and mDia1 expression and decreased PAK1 expression were detected in Nox1 y/− cells. Overexpression of S3A, a constitutively active cofilin mutant, partially recovered reduced migration of Nox1 y/− cells, suggesting that reduction in cofilin activity contributes to impaired migration of Nox1 y/− VSMCs. Conclusions— These results indicate that Nox1 plays a critical role in neointima formation by mediating VSMC migration, proliferation, and extracellular matrix production, and that cofilin is a major effector of Nox1-mediated migration. Inhibition of Nox1 may be an efficient strategy to suppress neointimal formation.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6045bd80edd366d250fd48b6d1061778Test
https://doi.org/10.1161/atvbaha.108.181925Test -
9دورية أكاديمية
المؤلفون: Shin, Yong Jae, Kim, Yong-Bae, Kim, Jeong-Ho
المصدر: Biochemistry and Molecular Medicine Faculty Publications
مصطلحات موضوعية: PAK1, CK2, Cancer, Casein Kinase II--metabolism, p21-Activated Kinases--metabolism, Cancer Biology, Cell Biology
الوصف: Activation of the p21-activated kinase 1 (PAK1) is achieved through a conformational change that converts an inactive PAK1 dimer to an active monomer. In this paper, we show that this change is necessary but not sufficient to activate PAK1 and that it is, rather, required for CK2-dependent PAK1S223 phosphorylation that converts a monomeric PAK1 into a catalytically active form. This phosphorylation appears to be essential for autophosphorylation at specific residues and overall activity of PAK1. A phosphomimetic mutation (S223E) bypasses the requirement for GTPases in PAK1 activation, whereas the constitutive activity of the PAK1 mutant (PAK1H83,86L), postulated to mimic GTPase-induced structural changes, is abolished by inhibition of S223 phosphorylation. Thus, S223 is likely accessible to CK2 upon conformational changes of PAK1 induced by GTPase-dependent and GTPase-independent stimuli, suggesting that S223 phosphorylation may play a key role in the final step of the PAK1 activation process. The physiological significance of this phosphorylation is reinforced by the observations that CK2 is responsible for epidermal growth factor–induced PAK1 activation and that inhibition of S223 phosphorylation abrogates PAK1-mediated malignant transformation of prostate epithelial cells. Taken together, these findings identify CK2 as an upstream activating kinase of PAK1, providing a novel mechanism for PAK1 activation.
وصف الملف: application/pdf
العلاقة: https://hsrc.himmelfarb.gwu.edu/smhs_biochem_facpubs/102Test; https://hsrc.himmelfarb.gwu.edu/cgi/viewcontent.cgi?article=1102&context=smhs_biochem_facpubsTest
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10دورية أكاديمية
المؤلفون: Chu, Ji, Pham, Ngoc T., Olate, Nicole, Kislitsyna, Karina, Day, Mary-Claire, LeTourneau, Phillip A., Kots, Alex, Stewart, Randolph H., Laine, Glen A., Cox, Charles S., Jr., Uray, Karen
المصدر: Biochemistry and Molecular Medicine Faculty Publications
مصطلحات موضوعية: Gastrointestinal Motility, Intestines--physiology, Muscle, Smooth--physiology, Myosin Light Chains--metabolism, p21-Activated Kinases--metabolism, Biochemistry, Biophysics, and Structural Biology
العلاقة: https://hsrc.himmelfarb.gwu.edu/smhs_biochem_facpubs/84Test; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543003Test/