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https://www.readbyqxmd.com/read/28919558/cellular-uptake-of-extracellular-vesicles-is-mediated-by-clathrin-independent-endocytosis-and-macropinocytosis
#1
Helena Costa Verdera, Jerney J Gitz-Francois, Raymond M Schiffelers, Pieter Vader
Recent evidence has established that extracellular vesicles (EVs), including exosomes and microvesicles, form an endogenous transport system through which biomolecules, including proteins and RNA, are exchanged between cells. This endows EVs with immense potential for drug delivery and regenerative medicine applications. Understanding the biology underlying EV-based intercellular transfer of cargo is of great importance for the development of EV-based therapeutics. Here, we sought to characterize the cellular mechanisms involved in EV uptake...
September 14, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28918037/a-novel-pak1-atf2-mir-132-signaling-axis-is-involved-in-the-hematogenous-metastasis-of-gastric-cancer-cells
#2
Funan Liu, Zhenguo Cheng, Xiaodong Li, Yanshu Li, Hongyan Zhang, Jiabin Li, Furong Liu, Huimian Xu, Feng Li
We, along with others, have shown previously that P21-activated kinase 1 (Pak1) plays a pivotal role in gastric cancer progression and metastasis. However, whether Pak1 controls gastric cancer metastasis by regulating microRNAs (miRNAs) has never been explored. Here, we report a novel mechanism of Pak1 in tumor metastasis. A detailed examination revealed that Pak1 interacts with and phosphorylates the serine 62 residue of ATF2 and then blocks its translocation into the nucleus. We also confirmed that ATF2 binds to the promoter of miR-132 and tightly regulates its transcription, thus explaining the regulatory mechanism of miR-132 by Pak1...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28854418/a-comparative-proteomic-analysis-of-erinacine-a-s-inhibition-of-gastric-cancer-cell-viability-and-invasiveness
#3
Hsing-Chun Kuo, Yur-Ren Kuo, Kam-Fai Lee, Meng-Chiao Hsieh, Cheng-Yi Huang, Yung-Yu Hsieh, Ko-Chao Lee, Hsiang-Lan Kuo, Li-Ya Lee, Wan-Ping Chen, Chin-Chu Chen, Shui-Yi Tung
Background / Aims: Erinacine A, isolated from the ethanol extract of the Hericium erinaceus mycelium, has been demonstrated as a new alternative anticancer medicine. Drawing upon current research, this study presents an investigation of the molecular mechanism of erinacine A inhibition associated with gastric cancer cell growth. METHODS: Cell viability was determined by Annexin V-FITC/propidium iodide staining and migration using a Boyden chamber assay to determine the effects of erinacine A treatment on the proliferation capacity and invasiveness of gastric cancer cells...
August 30, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28842430/switching-of-the-substrate-specificity-of-protein-tyrosine-phosphatase-n12-by-cyclin-dependent-kinase-2-phosphorylation-orchestrating-2-oncogenic-pathways
#4
Hui Li, Duxiao Yang, Shanglei Ning, Yinghui Xu, Fan Yang, Rusha Yin, Taihu Feng, Shouqing Han, Lu Guo, Pengju Zhang, Wenjie Qu, Renbo Guo, Chen Song, Peng Xiao, Chengjun Zhou, Zhigang Xu, Jin-Peng Sun, Xiao Yu
The protein tyrosine phosphatase N (PTPN)-12 is a multifunctional protein and has elicited much research attention because its decreased protein level has been associated with poor prognosis of several types of cancers. Recently, we have solved the crystal structure of the phosphatase domain of PTPN12, which disclosed a specific PTPN12-insert-loop harboring a cyclin-dependent kinase (CDK)-2 phosphorylation site. However, the functional significance of this phosphorylation is undefined. In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions...
August 24, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28814374/from-bench-laboratory-to-bed-hospital-home-how-to-explore-effective-natural-and-synthetic-pak1-blockers-longevity-promoters-for-cancer-therapy
#5
REVIEW
Hiroshi Maruta, Mok-Ryeon Ahn
PAK family kinases are RAC/CDC42-activated kinases that were first found in a soil amoeba 4 decades ago, and 2 decades later, were discovered in mammals as well. Since then at least 6 members of this family have been identified in mammals. One of them called PAK1 has been best studied so far, mainly because it is essential not only for malignant cell growth and metastasis, but also for many other diseases/disorders such as diabetes (type 2), AD (Alzheimer's disease), hypertension, and a variety of inflammatory or infectious diseases, which definitely shorten our lifespan...
August 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28806779/a-mutation-in-nischarin-causes-otitis-media-via-limk1-and-nf-%C3%AE%C2%BAb-pathways
#6
Michael Crompton, Tom Purnell, Hayley E Tyrer, Andrew Parker, Greg Ball, Rachel E Hardisty-Hughes, Richard Gale, Debbie Williams, Charlotte H Dean, Michelle M Simon, Ann-Marie Mallon, Sara Wells, Mahmood F Bhutta, Martin J Burton, Hilda Tateossian, Steve D M Brown
Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28803992/p-rex1-amplification-promotes-progression-of-cutaneous-melanoma-via-the-pak1-p38-mmp-2-pathway
#7
Jinhua Wang, Hajime Hirose, Guanhua Du, Kelly Chong, Eiji Kiyohara, Isaac P Witz, Dave S B Hoon
P-REX1 (PIP3-dependent Rac exchange factor-1) is a guanine nucleotide exchange factor that activates Rac by catalyzing exchange of GDP for GTP bound to Rac. Aberrant up-regulation of P-REX1 expression has a role in metastasis however, copy number (CN) and function of P-REX1 in cutaneous melanoma are unclear. To explore the role of P-REX1 in melanoma, SNP 6.0 and Exon 1.0 ST microarrays were assessed. There was a higher CN (2.82-fold change) of P-REX1 in melanoma cells than in melanocytes, and P-REX1 expression was significantly correlated with P-REX1 CN...
October 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28765528/pdx1-cre-driven-conditional-gene-depletion-suggests-pak4-as-dispensable-for-mouse-pancreas-development
#8
Miao Zhao, Parisa Rabieifar, Tânia D F Costa, Ting Zhuang, Audrey Minden, Matthias Löhr, Rainer Heuchel, Staffan Strömblad
Constitutive depletion of p21-activated kinase 4 (PAK4) in the mouse causes embryonic lethality associated with heart and brain defects. Given that conventional gene depletion of PAK1 or PAK3 caused functional deficits in the mouse pancreas, while gene depletion of PAK5 or PAK6 did not, we asked if PAK4 might have a functional role in pancreas development. We therefore introduced conditional, Pdx1-Cre-mediated, pancreatic PAK4 gene depletion in the mouse, verified by loss of PAK4 protein expression in the pancreas...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28748534/mir-130b-directly-targets-arhgap1-to-drive-activation-of-a-metastatic-cdc42-pak1-ap1-positive-feedback-loop-in-ewing-sarcoma
#9
Laura Satterfield, Ryan Shuck, Lyazat Kurenbekova, Wendy Allen-Rhoades, Dean Edwards, Shixia Huang, Kimal Rajapakshe, Cristian Coarfa, Lawrence A Donehower, Jason T Yustein
Ewing Sarcoma (ES) is a highly aggressive bone tumor with peak incidence in the adolescent population. It has a high propensity to metastasize, which is associated with dismal survival rates of approximately 25%. To further understand mechanisms of metastasis we investigated microRNA regulatory networks in ES. Our studies focused on miR-130b due to our analysis that enhanced expression of this microRNA has clinical relevance in multiple sarcomas, including ES. Our studies provide insights into a novel positive feedback network involving the direct regulation of miR-130b and activation of downstream signaling events contributing toward sarcoma metastasis...
November 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28747658/a-single-amino-acid-substitution-confers-b-cell-clonogenic-activity-to-the-hiv-1-matrix-protein-p17
#10
Cinzia Giagulli, Pasqualina D'Ursi, Wangxiao He, Simone Zorzan, Francesca Caccuri, Kristen Varney, Alessandro Orro, Stefania Marsico, Benoît Otjacques, Carlo Laudanna, Luciano Milanesi, Riccardo Dolcetti, Simona Fiorentini, Wuyuan Lu, Arnaldo Caruso
Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha)...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28707808/cytotoxic-necrotizing-factor-1-promotes-prostate-cancer-progression-through-activating-the-cdc42-pak1-axis
#11
Yaxiu Guo, Zhisong Zhang, Huiting Wei, Jingyu Wang, Junqiang Lv, Kai Zhang, Evan T Keller, Zhi Yao, Quan Wang
Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections and plays a role in prostatic carcinogenesis and prostate cancer (PCa) progression. However, the mechanisms through which UPEC promotes PCa development and progression are unclear. Cytotoxic necrotizing factor 1 (CNF1) is one of the most important UPEC toxins and its role in PCa progression has never been studied. We found that UPEC-secreted CNF1 promoted the migration and invasion of PCa cells and PCa metastasis. In vitro studies showed that CNF1 promotes pro-migratory and pro-invasive activity through entering PCa cells and activating Cdc42, which subsequently induced PAK1 phosphorylation and up-regulation of MMP-9 expression...
July 14, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28707321/expansion-of-bcr-abl1-cells-requires-pak2-but-not-pak1
#12
Leo Edlinger, Angelika Berger-Becvar, Ingeborg Menzl, Gregor Hoermann, Georg Greiner, Eva Grundschober, Zsuzsanna Bago-Horvath, Wael Al-Zoughbi, Gerald Hoefler, Christine Brostjan, Lars Gille, Richard Moriggl, Andreas Spittler, Veronika Sexl, Andrea Hoelbl-Kovacic
The p21-activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1(+) haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated...
July 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28692051/transcriptional-regulation-of-ataxia-telangiectasia-and-rad3-related-protein-by-activated-p21-activated-kinase-1-protects-keratinocytes-in-uv-b-induced-premalignant-skin-lesions
#13
S Beesetti, J Mavuluri, R P Surabhi, T M Oberyszyn, K Tober, R S Pitani, L D Joseph, G Venkatraman, S K Rayala
Sun-induced skin lesions, in particular actinic keratosis, are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) and invasive SCC if left untreated. Therefore, understanding the molecular mechanisms by which the ultraviolet-B (UV-B)-exposed cells are being protected and the signaling pathways that promote the progression of certain premalignant skin lesions to malignant lesions will permit us to prevent or cure skin cancers. In the current study, we found that phospho-p21-activated kinase-1 (Pak1) and Pak1 expression was high in clinical samples of sunlight-induced premalignant skin lesions assessed by immunohistochemistry...
July 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28655771/p115-rhogef-activates-the-rac1-gtpase-signaling-cascade-in-mcp1-chemokine-induced-vascular-smooth-muscle-cell-migration-and-proliferation
#14
COMPARATIVE STUDY
Nikhlesh K Singh, Jagadeesh Janjanam, Gadiparthi N Rao
Although the involvement of Rho proteins in the pathogenesis of vascular diseases is well studied, little is known about the role of their upstream regulators, the Rho guanine nucleotide exchange factors (RhoGEFs). Here, we sought to identify the RhoGEFs involved in monocyte chemotactic protein 1 (MCP1)-induced vascular wall remodeling. We found that, among the RhoGEFs tested, MCP1 induced tyrosine phosphorylation of p115 RhoGEF but not of PDZ RhoGEF or leukemia-associated RhoGEF in human aortic smooth muscle cells (HASMCs)...
August 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28638464/overexpression-of-pak1-correlates-with-aberrant-expression-of-emt-markers-and-poor-prognosis-in-non-small-cell-lung-cancer
#15
Zhiying Yang, Heran Wang, Longzheng Xia, Linda Oyang, Yujuan Zhou, Baihua Zhang, Xiaoyan Chen, Xia Luo, Qianjin Liao, Jianping Liang
Objective: p21-activated kinases (PAKs) are serine/threonine protein kinases. PAK1 and epithelial-mesenchymal transition (EMT) are key therapeutic targets in cancer. The clinical significance of PAK1 and its potential association with EMT phenotype in non-small cell lung cancer (NSCLC) was investigated. Methods: Immunohistochemistry was used to detect the expression of PAK1, and mesenchymal and epithelial markers (vimentin, N-cadherin, and E-cadherin) in 186 cases of NSCLC tissues and 50 cases of tumor-adjacent normal tissues...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28629331/depletion-of-p21-activated-kinase-1-up-regulates-the-immune-system-of-apc-%C3%A2-14-mice-and-inhibits-intestinal-tumorigenesis
#16
Nhi Huynh, Kai Wang, Mildred Yim, Chelsea J Dumesny, Mauro S Sandrin, Graham S Baldwin, Mehrdad Nikfarjam, Hong He
BACKGROUND: P21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up-regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC(∆14/+) mice. METHODS: The PAK1 KO APC(∆14/+) mice were generated by cross-breeding of PAK1 KO mice with APC(∆14/+) mice...
June 19, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28628382/unpaking-runx3-functions-both-sides-of-the-coin
#17
Arun Kumar, Sandhya Sundaram, Suresh K Rayala, Ganesh Venkatraman
Post translational modifications of RUNX3 have been shown to play an important role in directing RUNX3 functions. In this review we highlight the phosphorylation dependent functions of RUNX3 as regulated by PAK1 and its implications on tumorigenesis.
June 19, 2017: Small GTPases
https://www.readbyqxmd.com/read/28627240/quercetin-has-antimetastatic-effects-on-gastric-cancer-cells-via-the-interruption-of-upa-upar-function-by-modulating-nf-%C3%AE%C2%BAb-pkc-%C3%AE-erk1-2-and-ampk%C3%AE
#18
Hai Li, Chen Chen
Gastric cancer (GC) is a malignancy with few effective treatment options after metastasis occurs. Quercetin (Qu) intake has been associated with reduced incidence and slow development of GC, probably due to its anti-proliferative and apoptotic effects, but it is unclear whether Qu can inhibit the metastatic activity. The urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system plays an important role in cancer metastasis. In this study, we measured both uPA activity and uPAR expression in GC and pericarcinous tissues, and we investigated the correlation between uPAR expression and the migratory and invasive activities of various GC cell lines...
March 1, 2017: Integrative Cancer Therapies
https://www.readbyqxmd.com/read/28596575/infectious-pancreatic-necrosis-virus-enters-chse-214-cells-via-macropinocytosis
#19
Jorge Levican, Camila Miranda-Cárdenas, Ricardo Soto-Rifo, Francisco Aguayo, Aldo Gaggero, Oscar León
Infectious pancreatic necrosis virus (IPNV) is a non-enveloped virus belonging to the Birnaviridae family. IPNV produces an acute disease in salmon fingerlings, with high mortality rates and persistent infection in survivors. Although there are reports of IPNV binding to various cells, the viral receptor and entry pathways remain unknown. The aim of this study was to determine the endocytic pathway that allows for IPNV entry. We observed that IPNV stimulated fluid uptake and virus particles co-localysed with the uptake marker dextran in intracellular compartments, suggesting a role for macropinocytosis in viral entry...
June 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28574147/the-pak1-signalling-pathway-in-cardiac-disease-from-mechanistic-study-to-therapeutic-exploration
#20
REVIEW
Yanwen Wang, Shunyao Wang, Ming Lei, Mark Boyett, Hoyee Tsui, Wei Liu, Xin Wang
p21-activated kinase 1 (Pak1) is a member of the highly conserved family of serine/threonine protein kinases regulated by Ras-related small G-proteins, Cdc42/Rac1. It has been previously demonstrated to be involved in cardiac protection. Based on recent studies, this review assembles an overview of the role of Pak1 in cardiac diseases including disrupted Ca(2+) homoeostasis related cardiac arrhythmias, β-adrenergic stress and pressure overload-induced hypertrophy, and ischemia/reperfusion injury. These findings demonstrate the importance of Pak1 regulation through phosphorylation and transcriptional modification of hypertrophy and/or arrhythmia-related genes...
June 2, 2017: British Journal of Pharmacology
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