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Rho GTPases

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https://www.readbyqxmd.com/read/29331581/identification-and-characterization-of-arginine-finger-like-motifs-and-endosome-lysosome-basolateral-sorting-signals-within-ectopically-expressed-cira-a-coxiella-burnetii-type-iv-secreted-effector-protein
#1
Mary M Weber, Robert Faris, Erin J van Schaik, James E Samuel
Coxiella burnetii is an obligate intracellular pathogen that replicates in an endolysosome-like compartment termed the Coxiella-containing vacuole (CCV). Formation of this unique replicative niche requires delivery of bacterial effector proteins into the host cytosol where they mediate crucial interactions with the host. We previously identified an essential Dot/Icm effector, CirA that is required for intracellular replication and CCV formation. Furthermore, CirA was shown to stimulate the GTPase activity of RhoA in vitro...
January 10, 2018: Microbes and Infection
https://www.readbyqxmd.com/read/29331044/journey-of-oocyte-from-metaphase-i-to-metaphase-ii-stage-in-mammals
#2
Alka Sharma, Meenakshi Tiwari, Anumegha Gupta, Ashutosh N Pandey, Pramod K Yadav, Shail K Chaube
In mammals, journey from metaphase-I (M-I) to metaphase-II (M-II) is important since oocyte extrude first polar body (PB-I) and gets converted into haploid gamete. The molecular and cellular changes associated with meiotic cell cycle progression from M-I to M-II stage and extrusion of PB-I remain ill understood. Several factors drive oocyte meiosis from M-I to M-II stage. The mitogen-activated protein kinase3/1 (MAPK3/1), signal molecules and Rho family GTPases act through various pathways to drive cell cycle progression from M-I to M-II stage...
January 13, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29330094/p21-activated-kinase-signaling-in-cancer
#3
REVIEW
Chetan K Rane, Audrey Minden
The p21 Activated Kinases (PAKs) are a family of serine threonine kinases, that consist of 6 members, PAKs 1-6, which are positioned at an intersection of multiple signaling pathways implicated in oncogenesis. The PAKs were originally identified as protein kinases that function downstream of the Ras related Rho GTPases Cdc42 and Rac. PAK1 and PAK4, which belong to Group I and Group II PAKs, respectively, are most often associated with tumorigenesis. On account of their well characterized roles in cancer, several small molecule inhibitors are being developed to inhibit the PAKs, and there is interest in investigating their efficacy as either first line or adjuvant treatments for cancer...
January 9, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29329780/oncogenic-rac1-and-nras-drive-resistance-to-endoplasmic-reticulum-stress-through-mek-erk-signalling
#4
Michael D Bright, Paul A Clarke, Paul Workman, Faith E Davies
Cancer cells are able to survive under conditions that cause endoplasmic reticulum stress (ER-stress), and can adapt to this stress by upregulating cell-survival signalling pathways and down-regulating apoptotic pathways. The cellular response to ER-stress is controlled by the unfolded protein response (UPR). Small Rho family GTPases are linked to many cell responses including cell growth and apoptosis. In this study, we investigate the function of small GTPases in cell survival under ER-stress. Using siRNA screening we identify that RAC1 promotes cell survival under ER-stress in cells with an oncogenic N92I RAC1 mutation...
January 9, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29328460/terrein-inhibits-migration-of-human-breast-cancer-cells-via-inhibition-of-the-rho-and-rac-signaling-pathways
#5
Anongnard Kasorn, Fabien Loison, Thaned Kangsamaksin, Suchada Jongrungruangchok, Mathurose Ponglikitmongkol
Breast cancer is the most common cancer in women worldwide. Progression and aggressiveness of breast cancer is usually associated with its migration and invasion abilities. Recently, natural products with potential anticancer activity have become attractive candidates for alternative treatment of cancer. A fungal metabolite, terrein, isolated from the Aspergillus terreus has been revealed to exhibit selective anticancer activity; although this molecule has a variety of biological activities. The inhibitory effect on cell proliferation in hepatoma, keratinocytes, and lung cancer cells was due to cell cycle arrest without induction of apoptosis...
January 4, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29314205/cdc42-is-essential-for-both-articular-cartilage-degeneration-and-subchondral-bone-deterioration-in-experimental-osteoarthritis
#6
Xinhua Hu, Xing Ji, Mengting Yang, Shihao Fan, Jirong Wang, Meiping Lu, Wei Shi, Liu Mei, Chengyun Xu, Xueying Fan, Musaddique Hussain, Jingyu Du, Junsong Wu, Ximei Wu
Cdc42, a member of Rho family small GTPases, is critical for cartilage development. We investigated the roles of Cdc42 in osteoarthritis and explored the potential mechanism underlying Cdc42-mediated articular cartilage degeneration and subchondral bone deterioration. Cdc42 is highly expressed in both articular cartilage and subchondral bone in a mouse osteoarthritis model with surgical destabilisation of the medial meniscus (DMM) in the knee joints. Specifically, genetic disruption of Cdc42, knockdown of Cdc42 expression, or inhibition of Cdc42 activity robustly attenuates the DMM-induced destruction, hypertrophy, high expression of matrix metallopeptidase-13 and collagen X, and activation of Stat3 in articular cartilages...
January 3, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29313423/rho-guanosine-nucleotide-exchange-factors-are-not-such-bad-guys-after-all-in-cancera
#7
Javier Robles-Valero, L Francisco Lorenzo-Martín, Isabel Fernández-Pisonero, Xosé R Bustelo
Rho GDP/GTP exchange factors (GEFs), the enzymes that trigger the stimulation of Rho GTPases during cell signaling, are widely deemed as potential therapeutic targets owing to their protumorigenic functions. However, the sparse use of animal models has precluded a full understanding of their pathophysiological roles at the organismal level. In a recent article in Cancer Cell, we have reported that the Vav1 GEF unexpectedly acts as a tumor suppressor by mediating the noncatalytic nucleation of cytoplasmic complexes between the E3 ubiquitin ligase Cbl-b and the active Notch1 intracellular domain (ICN1)...
January 9, 2018: Small GTPases
https://www.readbyqxmd.com/read/29312635/lrp6-promotes-invasion-and-metastasis-of-colorectal-cancer-through-cytoskeleton-dynamics
#8
Qian Yao, Yu An, Wei Hou, Ya-Nan Cao, Meng-Fei Yao, Ning-Ning Ma, Lin Hou, Hong Zhang, Hai-Jing Liu, Bo Zhang
Low density lipoprotein (LDL) receptor-related protein-6 (LRP6) is an important co-receptor of Wnt pathway, which plays a predominant role in development and progression of colorectal cancer. Recently, dysregulation of LRP6 has proved to be involved in the progression of cancers, but its biological role and clinical significance in colorectal cancer remain unclear. In present study, we revealed that phosphorylation of LRP6 was aberrantly upregulated in colorectal carcinoma correlating with TNM or Dukes staging and worse prognosis...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29311115/miro-proteins-coordinate-microtubule-and-actin-dependent-mitochondrial-transport-and-distribution
#9
Guillermo López-Doménech, Christian Covill-Cooke, Davor Ivankovic, Els F Halff, David F Sheehan, Rosalind Norkett, Nicol Birsa, Josef T Kittler
In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho-GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double-knockout mouse embryos and single- and double-knockout embryonic fibroblasts, we demonstrate the essential and non-redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double-knockout cells...
January 8, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29310936/the-rhogap-stard13-controls-insulin-secretion-through-f-actin-remodeling
#10
Heike Naumann, Thomas Rathjen, Matthew N Poy, Francesca M Spagnoli
OBJECTIVE: Actin cytoskeleton remodeling is necessary for glucose-stimulated insulin secretion in pancreatic β-cells. A mechanistic understanding of actin dynamics in the islet is paramount to a better comprehension of β-cell dysfunction in diabetes. Here, we investigate the Rho GTPase regulator Stard13 and its role in F-actin cytoskeleton organization and islet function in adult mice. METHODS: We used Lifeact-EGFP transgenic animals to visualize actin cytoskeleton organization and dynamics in vivo in the mouse islets...
December 28, 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29297928/p21-activated-kinase-2-is-essential-in-maintenance-of-peripheral-foxp3-regulatory-t-cells
#11
Jinyong Choi, David Randall Pease, Siqi Chen, Bin Zhang, Hyewon Phee
The p21-activated kinase 2 (Pak2), an effector molecule of the Rho family GTPases Rac and Cdc42, regulates diverse functions of T cells. Previously, we showed that Pak2 is required for development and maturation of T cells in the thymus, including thymus-derived regulatory T cells (tTregs). However, whether Pak2 is required for functions of various subsets of peripheral T cells, such as naïve CD4 and helper T cell subsets including Foxp3+ regulatory T cells (Foxp3+Tregs), is unknown. To determine the role of Pak2 in CD4 T cells in the periphery, we generated inducible Pak2 knockout (KO) mice, in which Pak2 was deleted in CD4 T cells acutely by administration of tamoxifen...
January 3, 2018: Immunology
https://www.readbyqxmd.com/read/29296000/non-canonical-wnt-signaling-regulates-neural-stem-cell-quiescence-during-homeostasis-and-after-demyelination
#12
Manideep Chavali, Michael Klingener, Alexandros G Kokkosis, Yury Garkun, Sylwia Felong, Arianna Maffei, Adan Aguirre
Adult neural stem cells (NSCs) reside in a specialized microenvironment, the subventricular zone (SVZ), which provides them with unique signaling cues to control their basic properties and prevent their exhaustion. While the signaling mechanisms that regulate NSC lineage progression are well characterized, the molecular mechanisms that trigger the activation of quiescent NSCs during homeostasis and tissue repair are still unclear. Here, we uncovered that the NSC quiescent state is maintained by Rho-GTPase Cdc42, a downstream target of non-canonical Wnt signaling...
January 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29295957/the-depalmitoylase-apt1-directs-the-asymmetric-partitioning-of-notch-and-wnt-signaling-during-cell-division
#13
Ewa Stypulkowski, Irfan A Asangani, Eric S Witze
Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which, in turn, drives migration and metastasis. We report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell fate determinants Numb and β-catenin through the activity of the depalmitoylating enzyme APT1...
January 2, 2018: Science Signaling
https://www.readbyqxmd.com/read/29295922/cdc42-binds-pak4-via-an-extended-gtpase-effector-interface
#14
Byung Hak Ha, Titus J Boggon
The p21-activated kinase (PAK) group of serine/threonine kinases are downstream effectors of RHO GTPases and play important roles in regulation of the actin cytoskeleton, cell growth, survival, polarity, and development. Here we probe the interaction of the type II PAK, PAK4, with RHO GTPases. Using solution scattering we find that the full-length PAK4 heterodimer with CDC42 adopts primarily a compact organization. X-ray crystallography reveals the molecular nature of the interaction between PAK4 and CDC42 and shows that in addition to the canonical PAK4 CDC42/RAC interactive binding (CRIB) domain binding to CDC42 there are unexpected contacts involving the PAK4 kinase C-lobe, CDC42, and the PAK4 polybasic region...
January 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29286138/shrna-induced-silencing-of-ras-related-c3-botulinum-toxin-substrate-1-inhibits-the-proliferation-of-colon-cancer-cells-through-upregulation-of-bad-and-downregulation-of-cyclin-d1
#15
You-Sheng Huang, Na Jie, Yi-Xin Zhang, Ke-Jian Zou, Yang Weng
Ras-related C3 botulinum toxin substrate 1 (RAC1) is a member of the Rho family of small GTPases. Recent studies have reported that RAC1 serves an important role in colon cancer cell proliferation. The present study aimed to investigate the effects of RAC1 knockdown on cell proliferation, cell cycle progression and apoptosis of colon cancer cells. Lentivirus‑mediated short hairpin RNA (shRNA) was used to knockdown RAC1 expression in colon cancer cell lines, and cell proliferation, apoptosis, cell cycle progression were evaluated by MTT assays and flow cytometry...
December 22, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29279389/rsk2-drives-cell-motility-by-serine-phosphorylation-of-larg-and-activation-of-rho-gtpases
#16
Geng-Xian Shi, Won Seok Yang, Ling Jin, Michelle L Matter, Joe W Ramos
Directed migration is essential for cell motility in many processes, including development and cancer cell invasion. RSKs (p90 ribosomal S6 kinases) have emerged as central regulators of cell migration; however, the mechanisms mediating RSK-dependent motility remain incompletely understood. We have identified a unique signaling mechanism by which RSK2 promotes cell motility through leukemia-associated RhoGEF (LARG)-dependent Rho GTPase activation. RSK2 directly interacts with LARG and nucleotide-bound Rho isoforms, but not Rac1 or Cdc42...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29276004/missense-variants-in-rhobtb2-cause-a-developmental-and-epileptic-encephalopathy-in-humans-and-altered-levels-cause-neurological-defects-in-drosophila
#17
Jonas Straub, Enrico D H Konrad, Johanna Grüner, Annick Toutain, Levinus A Bok, Megan T Cho, Heather P Crawford, Holly Dubbs, Ganka Douglas, Rebekah Jobling, Diana Johnson, Bryan Krock, Mohamad A Mikati, Addie Nesbitt, Joost Nicolai, Meredith Phillips, Annapurna Poduri, Xilma R Ortiz-Gonzalez, Zöe Powis, Avni Santani, Lacey Smith, Alexander P A Stegmann, Constance Stumpel, Maaike Vreeburg, Anna Fliedner, Anne Gregor, Heinrich Sticht, Christiane Zweier
Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders...
December 13, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29250187/knockdown-of-rhotekin-2-expression-suppresses-proliferation-and-induces-apoptosis-in-colon-cancer-cells
#18
Xueqin Pang, Rui Li, Dongtao Shi, Xudong Pan, Chen Ma, Guangbo Zhang, Chuanyong Mu, Weichang Chen
Colon cancer is one of the most common malignant tumors in the human body, ranking second as a gastrointestinal tumor. It has a high incidence in Europe, America and China and more than 1 million new cases of colon cancer are reported worldwide each year. The incidence of colon cancer in China has increased from 12/0.1 million in the early 1970s to 56/0.1 million at present with an annual growth rate of 4.2%, which far exceeds the international level (2%). Rhotekin (RTKN) 2, a Rho-guanosine triphosphatase (GTPase) effector, has been reported to be anti-apoptotic...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29247652/aberrant-alternative-splicing-of-rhoa-is-associated-with-loss-of-its-expression-and-activity-in-diffuse-type-gastric-carcinoma-cells
#19
Shingo Miyamoto, Yuko Nagamura, Ayaka Nakabo, Akira Okabe, Kazuyoshi Yanagihara, Kiyoko Fukami, Ryuichi Sakai, Hideki Yamaguchi
RhoA is a member of Rho family small GTPases that regulates diverse cellular functions. Recent large-scale sequencing studies have identified recurrent somatic mutations of RHOA in diffuse-type gastric carcinoma (DGC), indicating that RHOA is a driver of DGC. In this study, we investigated the possible abnormalities of RHOA in a panel of gastric carcinoma (GC) cell lines. Pulldown assay and immunoblot analysis showed that the activity and expression of RhoA were detectable in all GC cell lines tested, except for two DGC cell lines, HSC-59 and GSU...
December 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29246246/rho-gtpases-as-therapeutic-targets-in-alzheimer-s-disease
#20
REVIEW
Byron J Aguilar, Yi Zhu, Qun Lu
The progress we have made in understanding Alzheimer's disease (AD) pathogenesis has led to the identification of several novel pathways and potential therapeutic targets. Rho GTPases have been implicated as critical components in AD pathogenesis, but their various functions and interactions make understanding their complex signaling challenging to study. Recent advancements in both the field of AD and Rho GTPase drug development provide novel tools for the elucidation of Rho GTPases as a viable target for AD...
December 15, 2017: Alzheimer's Research & Therapy
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