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small GTPase Ras

Nicolas Bery, Terence H Rabbitts
Protein-protein interactions (PPIs) are principle biological processes that control normal cell growth, differentiation, and homeostasis but are also crucial in diseases such as malignancy, neuropathy, and infection. Despite the importance of PPIs in biology, this target class has been very challenging to convert to therapeutics. In the last decade, much progress has been made in the inhibition of PPIs involved in diseases, but many remain difficult such as RAS-effector interactions in cancers. We describe here a protocol for using Bioluminescence Resonance Energy Transfer 2 (BRET2)-based RAS biosensors to detect and characterize RAS PPI inhibition by macromolecules and small molecules...
February 15, 2019: Current Protocols in Cell Biology
Priyanka Prakash, John F Hancock, Alemayehu A Gorfe
Raf kinases are downstream effectors of small GTPase Ras. Mutations in Ras and Raf are associated with a variety of cancers and genetic disorders. Of the three Raf isoforms, cRaf is most frequently involved in tumor initiation by Ras. Cytosolic Raf is auto-inhibited and becomes active upon recruitment to the plasma membrane. Since the catalytic domain of Raf is its kinase domain, we ask the following: does the kinase domain of Raf has potential to interact with membrane and if yes, what role does the membrane interaction play? We present a model of cRaf kinase domain in complex with a heterogeneous membrane bilayer using atomistic molecular dynamics simulation...
February 14, 2019: Scientific Reports
Yu-Chung Chang, Wenjuan Su, Eun-Ah Cho, Hao Zhang, Qingqiu Huang, Mark R Philips, Jinhua Wu
RAP1-interacting adapter molecule (RIAM) mediates RAP1-induced integrin activation. The RAS-association (RA) segment of the RA-PH module of RIAM interacts with GTP-bound RAP1 and phosphoinositol 4,5 bisphosphate but this interaction is inhibited by the N-terminal segment of RIAM. Here we report the structural basis for the autoinhibition of RIAM by an intramolecular interaction between the IN region (aa 27-93) and the RA-PH module. We solved the crystal structure of IN-RA-PH to a resolution of 2.4-Å. The structure reveals that the IN segment associates with the RA segment and thereby suppresses RIAM:RAP1 association...
February 7, 2019: Proceedings of the National Academy of Sciences of the United States of America
Zheng Yang, Hanrui Chen, Man Shu, Yunjian Zhang, Ling Xue, Yuan Lin
Deleted in liver cancer 2 (DLC2) is a tumor suppressor, associated with various types of cancer. The aim of the present study was to analyze the expression of DLC2 in breast cancer, its clinical significance and its effect on breast cancer cell behavior. The expression of DLC2 was evaluated by immunohistochemistry in 131 cases of breast cancer. Associations among DLC2 expression and clinicopathological features were analyzed, and its effects on proliferation, motility, migration and invasion in DLC2-knockdown breast cancer cell lines were observed...
February 2019: Oncology Letters
Ryan Knihtila, Alicia Y Volmar, Flora Meilleur, Carla Mattos
Neutron protein crystallography (NPC) reveals the three-dimensional structures of proteins, including the positions of H atoms. The technique is particularly suited to elucidate ambiguous catalytic steps in complex biochemical reactions. While NPC uniquely complements biochemical assays and X-ray structural analyses by revealing the protonation states of ionizable groups at and around the active site of enzymes, the technique suffers from a major drawback: large single crystals must be grown to compensate for the relatively low flux of neutron beams...
February 1, 2019: Acta Crystallographica. Section F, Structural Biology Communications
Chih-Shia Lee, Liam C Lee, Tina L Yuan, Sirisha Chakka, Christof Fellmann, Scott W Lowe, Natasha J Caplen, Frank McCormick, Ji Luo
Oncogenic mutations in the small GTPase KRAS are frequently found in human cancers, and, currently, there are no effective targeted therapies for these tumors. Using a combinatorial siRNA approach, we analyzed a panel of KRAS mutant colorectal and pancreatic cancer cell lines for their dependency on 28 gene nodes that represent canonical RAS effector pathways and selected stress response pathways. We found that RAF node knockdown best differentiated KRAS mutant and KRAS WT cancer cells, suggesting RAF kinases are key oncoeffectors for KRAS addiction...
February 1, 2019: Proceedings of the National Academy of Sciences of the United States of America
Roman C Hillig, Brice Sautier, Jens Schroeder, Dieter Moosmayer, André Hilpmann, Christian M Stegmann, Nicolas D Werbeck, Hans Briem, Ulf Boemer, Joerg Weiske, Volker Badock, Julia Mastouri, Kirstin Petersen, Gerhard Siemeister, Jan D Kahmann, Dennis Wegener, Niels Böhnke, Knut Eis, Keith Graham, Lars Wortmann, Franz von Nussbaum, Benjamin Bader
Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form...
January 25, 2019: Proceedings of the National Academy of Sciences of the United States of America
Samantha D Heitz, David J Hamelin, Reece M Hoffmann, Nili Greenberg, Gilbert Salloum, Zahra Erami, Bassem D Khalil, Aliaksei Shymanets, Elizabeth A Steidle, Grace Q Gong, Bernd Nürnberg, John E Burke, Jack U Flanagan, Anne R Bresnick, Jonathan M Backer
Phosphoinositide 3-kinase β (PI3Kβ) is regulated by receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and small GTPases such as Rac1 and Rab5. Our lab previously identified two residues (Gln-596 and Ile-597) in the helical domain of the catalytic subunit (p110β) of PI3Kβ whose mutation disrupts binding to Rab5. To better define the Rab5-p110β interface, we performed alanine-scanning mutagenesis and analyzed Rab5 binding with an in vitro pulldown assay with GST-Rab5GTP Of the 35 p110β helical domain mutants assayed, 11 disrupted binding to Rab5 without affecting Rac1 binding, basal lipid kinase activity, or Gβγ-stimulated kinase activity...
January 18, 2019: Journal of Biological Chemistry
Emanuele Monteleone, Valeria Orecchia, Paola Corrieri, Davide Schiavone, Lidia Avalle, Enrico Moiso, Aurora Savino, Ivan Molineris, Paolo Provero, Valeria Poli
Breast cancer is a heterogeneous disease whose clinical management is very challenging. Although specific molecular features characterize breast cancer subtypes with different prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical Wingless-type MMTV Integration site (WNT) and the Signal Transducer and Activator of Transcription (STAT)3 pathways are often constitutively activated in breast tumors, and both can induce the small GTPase Ras Homolog Family Member U RhoU ...
January 16, 2019: Cancers
Saravana Babu Chidambaram, A G Rathipriya, Srinivasa Rao Bolla, Abid Bhat, Bipul Ray, Arehslly Marappa Mahalakshmi, Thamilarasan Manivasagam, Arokiasamy Justin Thenmozhi, Musthafa Mohamed Essa, Gilles J Guillemin, Ramesh Chandra, Meena Kishore Sakharkar
Dendritic spines are small, thin, specialized protrusions from neuronal dendrites, primarily localized in the excitatory synapses. Sophisticated imaging techniques revealed that dendritic spines are complex structures consisting of a dense network of cytoskeletal, transmembrane and scaffolding molecules, and numerous surface receptors. Molecular signaling pathways, mainly Rho and Ras family small GTPases pathways that converge on actin cytoskeleton, regulate the spine morphology and dynamics bi-directionally during synaptic activity...
January 14, 2019: Progress in Neuro-psychopharmacology & Biological Psychiatry
Yu-Wen Chen, Ying-Chieh Yeh, Hsueh-Fen Chen, Ruei-Ching Chen, Guan-Yu Lin, Yu-Ting Chen, Chung-Yu Lan
Candida albicans is an important fungal pathogen of humans. Rhb1 is a small GTPase of the Ras superfamily and is conserved from yeasts to humans. In C. albicans, Rhb1 regulates the expression of secreted protease 2, low nitrogen-mediated morphogenesis and biofilm formation. Moreover, our previous studies have indicated that Rhb1 is associated with the target of rapamycin (TOR) signaling pathway. In this study, we further explored the relationship between Rhb1 and drug susceptibility. The RHB1 deletion mutant exhibited reduced fluconazole susceptibility, and this phenotype occurred mainly through the increased gene expression and activity of efflux pumps...
January 11, 2019: FEMS Yeast Research
Francisco Llavero, Miriam Luque Montoro, Alazne Arrazola Sastre, David Fernández-Moreno, Hadriano M Lacerda, Luis A Parada, Alejandro Lucia, José L Zugaza
We recently uncovered a regulatory pathway of the muscle isoform of glycogen phosphorylase (PYGM) that plays an important role in regulating immune function in T cells. Here, using various enzymatic, pulldown, and immunoprecipitation assays, we describe signaling crosstalk between the small GTPases RAS and RAP1A, member of RAS oncogene family (RAP1) in human Kit 225 lymphoid cells which, in turn, is regulated by the epidermal growth factor receptor (EGFR). We found that this communication bridge is essential for glycogen phosphorylase (PYG) activation through the canonical pathway, since this enzyme is inactive in the absence of adenylyl cyclase type 6 (ADCY6)...
January 15, 2019: Journal of Biological Chemistry
Jihoon Kim, Sangkyu Lee, Kanghoon Jung, Won Chan Oh, Nury Kim, Seungkyu Son, YoungJu Jo, Hyung-Bae Kwon, Won Do Heo
Ras and Rho small GTPases are critical for numerous cellular processes including cell division, migration, and intercellular communication. Despite extensive efforts to visualize the spatiotemporal activity of these proteins, achieving the sensitivity and dynamic range necessary for in vivo application has been challenging. Here, we present highly sensitive intensiometric small GTPase biosensors visualizing the activity of multiple small GTPases in single cells in vivo. Red-shifted sensors combined with blue light-controllable optogenetic modules achieved simultaneous monitoring and manipulation of protein activities in a highly spatiotemporal manner...
January 14, 2019: Nature Communications
Yuanyuan Feng, Maolin Ma, Xiaojiao Zhang, Die Liu, Lei Wang, Cen Qian, Guoqing Wei, Baojian Zhu
Ras-related C3 botulinum toxin substrate 1 (Rac1) participates in many biological processes. In this study, a Rac1 gene was identified in the crayfish Procambarus clarkii with an open reading frame of 579 bp that encoded 192 amino acids. This predicted 21.4 kDa protein was highly homologous to those in other invertebrates. Real-time PCR analysis revealed that Pc-Rac1 was expressed in all examined tissues with the highest expression level in hemocytes. The transcriptional expression level of Pc-Rac1 was significantly upregulated in hemocytes and hepatopancreas after lipopolysaccharide (LPS) or polyinosinic: polycytidylic acid (poly I: C) induction...
January 9, 2019: Fish & Shellfish Immunology
Kanoko Umezawa, Tatsuya Nagano, Kazuyuki Kobayashi, Ryota Dokuni, Masahiro Katsurada, Masatsugu Yamamoto, Yoko Yoshikawa, Tohru Kataoka, Yoshihiro Nishimura
BACKGROUND: We have shown that phospholipase Cε (PLCε), an effector of Ras and Rap1 small GTPases, plays pivotal roles in inflammation and inflammation-associated carcinogenesis by augmenting proinflammatory cytokine production from epithelial cells of various organs. The purpose of this study is to analyze its role in neutrophilic alveolar inflammation accompanying acute lung injury (ALI), focusing on that in alveolar epithelial cells (AECs), which are known to make a major contribution to the pathogenesis of ALI...
January 11, 2019: Respiratory Research
Edward J Goetzl, Fanny M Elahi, Maja Mustapic, Dimitrios Kapogiannis, Moira Pryhoda, Anah Gilmore, Kimberly A Gorgens, Bradley Davidson, Anne-Charlotte Granholm, Aurélie Ledreux
Neuron-derived exosomes (NDEs) were enriched by anti-L1CAM antibody immunoabsorption from plasmas of subjects ages 18-26 yr within 1 wk after a sports-related mild traumatic brain injury (acute mTBI) ( n = 18), 3 mo or longer after the last of 2-4 mTBIs (chronic mTBI) ( n = 14) and with no recent history of TBI (controls) ( n = 21). Plasma concentrations of NDEs, assessed by counts and levels of extracted exosome marker CD81, were significantly depressed by a mean of 45% in acute mTBI ( P < 0.0001), but not chronic mTBI, compared with controls...
January 3, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Anne R Bresnick, Jonathan M Backer
The phosphoinositide 3-kinase (PI3K) family includes 8 distinct catalytic subunits and seven regulatory subunits. Only two PI3Ks are directly regulated downstream from G Protein-Coupled Receptors (GPCRs): the Class I enzymes PI3Kβ and PI3Kγ. Both enzymes produce phosphatidylinositol (3,4,5)P3in vivo, and are regulated by both heterotrimeric G-proteins and small GTPases from the Ras or Rho families. However, PI3Kβ is also regulated by direct interactions with receptor tyrosine kinases (RTKs) and their tyrosine phosphorylated substrates, and like the Class II and III PI3Ks, it binds activated Rab5...
January 2, 2019: Endocrinology
Diana Casique-Aguirre, Paola Briseño-Díaz, Ponciano García-Gutiérrez, Claudia Haydée González-de la Rosa, Reyna Sara Quintero-Barceinas, Arturo Rojo-Domínguez, Irene Vergara, Luis Alberto Medina, José Correa-Basurto, Martiniano Bello, Rosaura Hernández-Rivas, María Del RocioThompson-Bonilla, Miguel Vargas
BACKGROUND: The GTPase KRas4B has been utilized as a principal target in the development of anticancer drugs. PDE6δ transports KRas4B to the plasma membrane, where it is released to activate various signaling pathways required for the initiation and maintenance of cancer. Therefore, identifying new small molecules that prevent activation of this GTPase by stabilizing the KRas4B-PDE6δ molecular complex is a practical strategy to fight against cancer. METHODS: The crystal structure of the KRas4B-PDE6δ heterodimer was employed to locate possible specific binding sites at the protein-protein interface region...
December 29, 2018: BMC Cancer
Kentaro Umeda, Manabu Negishi, Hironori Katoh
The appropriate development and regulation of neuronal morphology are important to establish functional neuronal circuits and enable higher brain function of the central nervous system. R-Ras, a member of the Ras family of small GTPases, plays crucial roles in the regulation of axonal morphology, including outgrowth, branching, and guidance. GTP-bound activated R-Ras reorganizes actin filaments and microtubules through interactions with its downstream effectors, leading to the precise control of axonal morphology...
March 2019: Biochemistry and Biophysics Reports
Takeshi Sekiguchi, Nobuaki Furuno, Takashi Ishii, Eiji Hirose, Fumiko Sekiguchi, Yonggang Wang, Hideki Kobayashi
Small Ras-like GTPases act as molecular switches for various signal transduction pathways. RagA, RagB/RagC, and RagD are small Ras-like GTPases that play regulatory roles in mTORC1. Lack of proper activation of mTORC1 can lead to diseases such as cancer and diabetes. In this study, we found an interaction between RagA and WDR35. Mutations of WDR35 may cause genetic diseases including Sensenbrenner syndrome. WDR35 seems to be a hedgehog signaling protein with a possible ciliary function and a possible upstream regulator of RagA...
December 20, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
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