keyword
https://read.qxmd.com/read/38454952/ral-1-signaling-regulates-lipid-composition-in-c-elegans
#1
JOURNAL ARTICLE
You Wu, Minjung Lee, A Sena Mutlu, Meng Wang, David J Reiner
Signaling by the Ral small GTPase is poorly understood in vivo . Caenorhabditis elegans animals with constitutively activated RAL-1 or deficient for the inhibitory RalGAP, HGAP-1 /2, display pale intestines. Staining with Oil Red O detected decreased intestinal lipids in the hgap-1 deletion mutant relative to the wild type. Constitutively activated RAL-1 decreased lipid detected by stimulated Raman scattering (SRS) microscopy, a label-free method of detecting lipid by laser excitation and detection. A signaling-deficient missense mutant for RAL-1 also displayed reduced lipid staining via SRS...
2024: microPublication. Biology
https://read.qxmd.com/read/38141762/toxoplasma-gondii-mitochondrial-association-factor-1b-interactome-reveals-novel-binding-partners-including-ral-gtpase-accelerating-protein-%C3%AE-1
#2
JOURNAL ARTICLE
Cameron J Powell, Meredith L Jenkins, Tara B Hill, Matthew L Blank, Leah F Cabo, Lexie R Thompson, John E Burke, Jon P Boyle, Martin J Boulanger
The intracellular parasite, Toxoplasma gondii, has developed sophisticated molecular strategies to subvert host processes and promote growth and survival. During infection, T. gondii replicates in a parasitophorous vacuole (PV) and modulates host functions through a network of secreted proteins. Of these, Mitochondrial Association Factor 1b (MAF1b) recruits host mitochondria to the PV, a process which confers an in vivo growth advantage, though the precise mechanisms remain enigmatic. To address this knowledge gap, we mapped the MAF1b interactome in human fibroblasts using a commercial Yeast-2-hybrid (Y2H) screen, which revealed several previously unidentified binding partners including the GAP domain of Ral GTPase Accelerating Protein α1 (RalGAPα1(GAP))...
December 21, 2023: Journal of Biological Chemistry
https://read.qxmd.com/read/37116704/ral-gtpase-promotes-metastasis-of-pancreatic-ductal-adenocarcinoma-via-elevation-of-tgf-%C3%AE-1-production
#3
JOURNAL ARTICLE
Mingxin Cao, Xinming Li, Duc-Anh Trinh, Shingo Yoshimachi, Kota Goto, Natsumi Sakata, Masaharu Ishida, Hideo Ohtsuka, Michiaki Unno, Yuxia Wang, Ryutaro Shirakawa, Hisanori Horiuchi
Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAPβ-deficient PDAC cells with highly activated Ral GTPases. Array analysis and enzyme-linked immunosorbent assays revealed increased expression and secretion of TGF-β1 in RalGAPβ-deficient PDAC cells compared to control cells...
April 26, 2023: Journal of Biological Chemistry
https://read.qxmd.com/read/35116360/low-expression-of-ralgaps-associates-with-the-poorer-overall-survival-of-head-and-neck-squamous-cell-carcinoma
#4
JOURNAL ARTICLE
Shan Liu, Congyu Shi, Xiaoyi Wang, Xiangrui Ma, Pan Gao
BACKGROUND: The role of Ral and RalGAPs on the progression of head and neck squamous cell carcinoma (HNSC) remains unclear. METHODS: The predesigned siRNAs against RalGAPs were transfected into cells to evaluate the effect on RalA activation. The Data from TCGA and GTEx were combined to analyze the pan-cancer gene expression of RalA and RalGAPs in cancer and adjacent normal tissues. Kaplan-Meier analysis was used to assess the predictive value of RalA and RalGAPs expression on the overall survival of patients with HNSC...
December 2021: Translational Cancer Research
https://read.qxmd.com/read/34767674/dysregulation-of-rala-signaling-through-dual-regulatory-mechanisms-exerts-its-oncogenic-functions-in-hepatocellular-carcinoma
#5
JOURNAL ARTICLE
Lu Tian, Luqing Zhao, Karen Man-Fong Sze, Charles Shing Kam, Vanessa Sheung-In Ming, Xia Wang, Vanilla Xin Zhang, Daniel Wai-Hung Ho, Tan-To Cheung, Lo-Kong Chan, Irene Oi-Lin Ng
BACKGROUND AND AIMS: Ras-like (Ral) small guanosine triphosphatases (GTPases), RalA and RalB, are proto-oncogenes directly downstream of Ras and cycle between the active guanosine triphosphate-bound and inactive guanosine diphosphate-bound forms. RalGTPase-activating protein (RalGAP) complex exerts a negative regulation. Currently, the role of Ral up-regulation in cancers remains unclear. We aimed to examine the clinical significance, functional implications, and underlying mechanisms of RalA signaling in HCC...
November 12, 2021: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://read.qxmd.com/read/34706226/subtractive-crispr-screen-identifies-the-atg16l1-vacuolar-atpase-axis-as-required-for-non-canonical-lc3-lipidation
#6
JOURNAL ARTICLE
Rachel Ulferts, Elena Marcassa, Lewis Timimi, Liam Changwoo Lee, Andrew Daley, Beatriz Montaner, Suzanne Dawn Turner, Oliver Florey, John Kenneth Baillie, Rupert Beale
Although commonly associated with autophagosomes, LC3 can also be recruited to membranes by covalent lipidation in a variety of non-canonical contexts. These include responses to ionophores such as the M2 proton channel of influenza A virus. We report a subtractive CRISPR screen that identifies factors required for non-canonical LC3 lipidation. As well as the enzyme complexes directly responsible for LC3 lipidation in all contexts, we show the RALGAP complex is important for M2-induced, but not ionophore drug-induced, LC3 lipidation...
October 26, 2021: Cell Reports
https://read.qxmd.com/read/34074494/the-ral-signaling-network-cancer-and-beyond
#7
REVIEW
Lisa H Apken, Andrea Oeckinghaus
The RAL proteins RALA and RALB belong to the superfamily of small RAS-like GTPases (guanosine triphosphatases). RAL GTPases function as molecular switches in cells by cycling through GDP- and GTP-bound states, a process which is regulated by several guanine exchange factors (GEFs) and two heterodimeric GTPase activating proteins (GAPs). Since their discovery in the 1980s, RALA and RALB have been established to exert isoform-specific functions in central cellular processes such as exocytosis, endocytosis, actin organization and gene expression...
2021: International Review of Cell and Molecular Biology
https://read.qxmd.com/read/34009715/ral-gtpase-activating-protein-regulates-the-malignancy-of-pancreatic-ductal-adenocarcinoma
#8
JOURNAL ARTICLE
Shingo Yoshimachi, Ryutaro Shirakawa, Mingxin Cao, Duc Anh Trinh, Pan Gao, Natsumi Sakata, Kento Miyazaki, Kota Goto, Takayuki Miura, Kyohei Ariake, Shimpei Maeda, Kunihiro Masuda, Masaharu Ishida, Hideo Ohtsuka, Michiaki Unno, Hisanori Horiuchi
The small GTPases RalA and RalB are members of the Ras family and activated downstream of Ras. Ral proteins are found in GTP-bound active and GDP-bound inactive forms. The activation process is executed by guanine nucleotide exchange factors, while inactivation is mediated by GTPase-activating proteins (GAPs). RalGAPs are complexes that consist of a catalytic α1 or α2 subunit together with a common β subunit. Several reports implicate the importance of Ral in pancreatic ductal adenocarcinoma (PDAC). However, there are few reports on the relationship between levels of RalGAP expression and malignancy in PDAC...
August 2021: Cancer Science
https://read.qxmd.com/read/32004447/bi-allelic-variants-in-ralgapa1-cause-profound-neurodevelopmental-disability-muscular-hypotonia-infantile-spasms-and-feeding-abnormalities
#9
JOURNAL ARTICLE
Matias Wagner, Yuliya Skorobogatko, Ben Pode-Shakked, Cynthia M Powell, Bader Alhaddad, Annette Seibt, Ortal Barel, Gali Heimer, Chen Hoffmann, Laurie A Demmer, Yezmin Perilla-Young, Marc Remke, Dagmar Wieczorek, Tharsini Navaratnarajah, Peter Lichtner, Dirk Klee, Hanan E Shamseldin, Fuad Al Mutairi, Ertan Mayatepek, Tim Strom, Thomas Meitinger, Fowzan S Alkuraya, Yair Anikster, Alan R Saltiel, Felix Distelmaier
Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms ...
February 6, 2020: American Journal of Human Genetics
https://read.qxmd.com/read/31329042/ral-gtpase-activation-by-downregulation-of-ralgap-enhances-oral-squamous-cell-carcinoma-progression
#10
JOURNAL ARTICLE
P Gao, S Liu, R Yoshida, C Y Shi, S Yoshimachi, N Sakata, K Goto, T Kimura, R Shirakawa, H Nakayama, J Sakata, S Kawashiri, K Kato, X Y Wang, H Horiuchi
Ral small GTPases, consisting of RalA and RalB, are members of the Ras family. Their activity is upregulated by RalGEFs. Since several RalGEFs are downstream effectors of Ras, Ral is activated by the oncogenic mutant Ras. Ral is negatively regulated by RalGAP complexes that consist of a catalytic α1 or α2 subunit and its common partner β subunit and similarly regulate the activity of RalA as well as RalB in vitro. Ral plays an important role in the formation and progression of pancreatic and lung cancers...
August 2019: Journal of Dental Research
https://read.qxmd.com/read/31058283/downregulation-of-ralgtpase-activating-protein-promotes-invasion-of-prostatic-epithelial-cells-and-progression-from-intraepithelial-neoplasia-to-cancer-during-prostate-carcinogenesis
#11
JOURNAL ARTICLE
Masayuki Uegaki, Yuki Kita, Ryutaro Shirakawa, Yuki Teramoto, Yuki Kamiyama, Ryoichi Saito, Takeshi Yoshikawa, Hiromasa Sakamoto, Takayuki Goto, Shusuke Akamatsu, Toshinari Yamasaki, Takahiro Inoue, Akira Suzuki, Hisanori Horiuchi, Osamu Ogawa, Takashi Kobayashi
RalGTPase-activating protein (RalGAP) is an important negative regulator of small GTPases RalA/B that mediates various oncogenic signaling pathways in various cancers. Although the Ral pathway has been implicated in prostate cancer (PCa) development and progression, the significance of RalGAP in PCa has been largely unknown. We examined RalGAPα2 expression using immunohistochemistry on two independent tissue microarray sets. Both datasets demonstrated that the expression of RalGAPα2 was significantly downregulated in PCa tissues compared to adjacent benign prostatic epithelia...
December 31, 2019: Carcinogenesis
https://read.qxmd.com/read/29915037/rala-controls-glucose-homeostasis-by-regulating-glucose-uptake-in-brown-fat
#12
JOURNAL ARTICLE
Yuliya Skorobogatko, Morgan Dragan, Claudia Cordon, Shannon M Reilly, Chao-Wei Hung, Wenmin Xia, Peng Zhao, Martina Wallace, Denise E Lackey, Xiao-Wei Chen, Olivia Osborn, Juliane G Bogner-Strauss, Dan Theodorescu, Christian M Metallo, Jerrold M Olefsky, Alan R Saltiel
Insulin increases glucose uptake into adipose tissue and muscle by increasing trafficking of the glucose transporter Glut4. In cultured adipocytes, the exocytosis of Glut4 relies on activation of the small G protein RalA by insulin, via inhibition of its GTPase activating complex RalGAP. Here, we evaluate the role of RalA in glucose uptake in vivo with specific chemical inhibitors and by generation of mice with adipocyte-specific knockout of RalGAPB. RalA was profoundly activated in brown adipose tissue after feeding, and its inhibition prevented Glut4 exocytosis...
July 24, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/25509336/-identification-of-ralgaps-and-their-downregulation-in-invasive-bladder-cancer
#13
REVIEW
Ryutaro Shirakawa, Hisanori Horiuchi
No abstract text is available yet for this article.
October 2014: Seikagaku. the Journal of Japanese Biochemical Society
https://read.qxmd.com/read/24814574/a-role-for-ral-gtpase-activating-protein-subunit-%C3%AE-in-mitotic-regulation
#14
JOURNAL ARTICLE
Nicolas Personnic, Goran Lakisic, Edith Gouin, Alix Rousseau, Alexis Gautreau, Pascale Cossart, Hélène Bierne
Ral proteins are small GTPases that play critical roles in normal physiology and in oncogenesis. There is little information on the GTPase-activating proteins (GAPs) that downregulate their activity. Here, we provide evidence that the noncatalytic β subunit of RalGAPα1/2 β complexes is involved in mitotic control. RalGAPβ localizes to the Golgi and nucleus during interphase, and relocalizes to the mitotic spindle and cytokinetic intercellular bridge during mitosis. Depletion of RalGAPβ causes chromosome misalignment and decreases the amount of mitotic cyclin B1, disturbing the metaphase-to-anaphase transition...
July 2014: FEBS Journal
https://read.qxmd.com/read/24768767/garnl1-a-major-ralgap-%C3%AE-subunit-in-skeletal-muscle-regulates-insulin-stimulated-rala-activation-and-glut4-trafficking-via-interaction-with-14-3-3-proteins
#15
JOURNAL ARTICLE
Qiaoli Chen, Chao Quan, Bingxian Xie, Liang Chen, Shuilian Zhou, Rachel Toth, David G Campbell, Shuangshuang Lu, Ryutaro Shirakawa, Hisanori Horiuchi, Chaojun Li, Zhongzhou Yang, Carol MacKintosh, Hong Yu Wang, Shuai Chen
Insulin and muscle contraction each stimulate translocation of the glucose transporter GLUT4 to the plasma membrane in skeletal muscle, an important process regulating whole-body glucose homeostasis. RalA mediates insulin-stimulated GLUT4 translocation; however, it is unclear how this small GTPase is regulated in skeletal muscle in response to insulin. Here, we identified GARNL1/RalGAPα1, a major α subunit of the Ral-GTPase activating protein in skeletal muscle, as a protein whose phosphorylation and binding to the regulatory 14-3-3 proteins is stimulated by insulin and also by muscle contraction...
August 2014: Cellular Signalling
https://read.qxmd.com/read/24596212/ralgaps-regulate-mtorc1-signaling
#16
(no author information available yet)
A RalGAP-RalB pathway regulates mTORC1 activity independent of Rheb.
March 2014: Cancer Discovery
https://read.qxmd.com/read/24389102/ral-and-rheb-gtpase-activating-proteins-integrate-mtor-and-gtpase-signaling-in-aging-autophagy-and-tumor-cell-invasion
#17
JOURNAL ARTICLE
Timothy D Martin, Xiao-Wei Chen, Rebecca E W Kaplan, Alan R Saltiel, Cheryl L Walker, David J Reiner, Channing J Der
Diverse environmental cues converge on and are integrated by the mTOR signaling network to control cellular growth and homeostasis. The mammalian Tsc1-Tsc2 GTPase activating protein (GAP) heterodimer is a critical negative regulator of Rheb and mTOR activation. The RalGAPα-RalGAPβ heterodimer shares sequence and structural similarity with Tsc1-Tsc2. Unexpectedly, we observed that C. elegans expresses orthologs for the Rheb and RalA/B GTPases and for RalGAPα/β, but not Tsc1/2. This prompted our investigation to determine whether RalGAPs additionally modulate mTOR signaling...
January 23, 2014: Molecular Cell
https://read.qxmd.com/read/23386617/negative-regulation-of-the-ralgap-complex-by-14-3-3
#18
JOURNAL ARTICLE
Dara Leto, Maeran Uhm, Anja Williams, Xiao-wei Chen, Alan R Saltiel
RGC1 and RGC2 comprise a functional RalGAP complex (RGC) that suppresses RalA activity. The PI3-kinase/Akt signaling pathway activates RalA through phosphorylation-mediated inhibition of the RGC. Here we identify a novel phosphorylation-dependent interaction between 14-3-3 and the RGC. 14-3-3 binds to the complex through an Akt-phosphorylated residue, threonine 715, on RGC2. Interaction with 14-3-3 does not alter in vitro activity of the GTPase-activating protein complex. However, blocking the interaction between 14-3-3 and RGC2 in cells increases suppression of RalA activity by the RGC, suggesting that 14-3-3 inhibits the complex through a non-catalytic mechanism...
March 29, 2013: Journal of Biological Chemistry
https://read.qxmd.com/read/22450745/downregulation-of-ral-gtpase-activating-protein-promotes-tumor-invasion-and-metastasis-of-bladder-cancer
#19
JOURNAL ARTICLE
R Saito, R Shirakawa, H Nishiyama, T Kobayashi, M Kawato, T Kanno, K Nishizawa, Y Matsui, T Ohbayashi, M Horiguchi, T Nakamura, T Ikeda, K Yamane, E Nakayama, E Nakamura, Y Toda, T Kimura, T Kita, O Ogawa, H Horiuchi
The small GTPase Ral is known to be highly activated in several human cancers, such as bladder, colon and pancreas cancers. It is reported that activated Ral is involved in cell proliferation, migration and metastasis of bladder cancer. This protein is activated by Ral guanine nucleotide exchange factors (RalGEFs) and inactivated by Ral GTPase-activating proteins (RalGAPs), the latter of which consist of heterodimers containing a catalytic α1 or α2 subunit and a common β subunit. In Ras-driven cancers, such as pancreas and colon cancers, constitutively active Ras mutant activates Ral through interaction with RalGEFs, which contain the Ras association domain...
February 14, 2013: Oncogene
https://read.qxmd.com/read/19520869/tuberous-sclerosis-tumor-suppressor-complex-like-complexes-act-as-gtpase-activating-proteins-for-ral-gtpases
#20
JOURNAL ARTICLE
Ryutaro Shirakawa, Shuya Fukai, Mitsunori Kawato, Tomohito Higashi, Hirokazu Kondo, Tomoyuki Ikeda, Ei Nakayama, Katsuya Okawa, Osamu Nureki, Takeshi Kimura, Toru Kita, Hisanori Horiuchi
The small GTPases RalA and RalB are multifunctional proteins regulating a variety of cellular processes. Like other GTPases, the activity of Ral is regulated by the opposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Although several RalGEFs have been identified and characterized, the molecular identity of RalGAP remains unknown. Here, we report the first molecular identification of RalGAPs, which we have named RalGAP1 and RalGAP2. They are large heterodimeric complexes, each consisting of a catalytic alpha1 or alpha2 subunit and a common beta subunit...
August 7, 2009: Journal of Biological Chemistry
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