scholarly journals Tumor Suppression of Ras GTPase-Activating Protein RASA5 through Antagonizing Ras Signaling Perturbation in Carcinomas

iScience ◽  
2019 ◽  
Vol 21 ◽  
pp. 1-18 ◽  
Author(s):  
Lili Li ◽  
Yichao Fan ◽  
Xin Huang ◽  
Jie Luo ◽  
Lan Zhong ◽  
...  
Keyword(s):  
Tumor Suppression ◽  
Ras Signaling ◽  
Gtpase Activating Protein ◽  
Ras Gtpase

scholarly journals Ras GTPase-Activating Protein Regulation of Actin Cytoskeleton and Hyphal Polarity in Aspergillus nidulans

2007 ◽  
Vol 7 (1) ◽  
pp. 141-153 ◽  
Author(s):  
Laura Harispe ◽  
Cecilia Portela ◽  
Claudio Scazzocchio ◽  
Miguel A. Peñalva ◽  
Lisette Gorfinkiel
Keyword(s):  
Carbon Source ◽  
Actin Cytoskeleton ◽  
Aspergillus Nidulans ◽  
Fluorescent Protein ◽  
Protein Domain ◽  
Ras Signaling ◽  
Wild Type ◽  
Gtpase Activating Protein ◽  
Ras Gtpase ◽  
Polarity Establishment

ABSTRACT Aspergillus nidulans gapA1, a mutation leading to compact, fluffy colonies and delayed polarity establishment, maps to a gene encoding a Ras GTPase-activating protein. Domain organization and phylogenetic analyses strongly indicate that GapA regulates one or more “true” Ras proteins. A gapAΔ strain is viable. gapA colonies are more compact than gapA1 colonies and show reduced conidiation. gapAΔ strains have abnormal conidiophores, characterized by the absence of one of the two layers of sterigmata seen in the wild type. gapA transcript levels are very low in conidia but increase during germination and reach their maximum at a time coincident with germ tube emergence. Elevated levels persist in hyphae. In germinating conidiospores, gapAΔ disrupts the normal coupling of isotropic growth, polarity establishment, and mitosis, resulting in a highly heterogeneous cell population, including malformed germlings and a class of giant cells with no germ tubes and a multitude of nuclei. Unlike wild-type conidia, gapAΔ conidia germinate without a carbon source. Giant multinucleated spores and carbon source-independent germination have been reported in strains carrying a rasA dominant active allele, indicating that GapA downregulates RasA. gapAΔ cells show a polarity maintenance defect characterized by apical swelling and subapical branching. The strongly polarized wild-type F-actin distribution is lost in gapAΔ cells. As GapA-green fluorescent protein shows cortical localization with strong predominance at the hyphal tips, we propose that GapA-mediated downregulation of Ras signaling at the plasma membrane of these tips is involved in the polarization of the actin cytoskeleton that is required for hyphal growth and, possibly, for asexual morphogenesis.

Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice

Blood ◽  
2009 ◽  
Vol 114 (17) ◽  
pp. 3629-3632 ◽  
Author(s):  
Briony A. Cutts ◽  
Anna-Karin M. Sjogren ◽  
Karin M. E. Andersson ◽  
Annika M. Wahlstrom ◽  
Christin Karlsson ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cells ◽  
Myeloproliferative Disorders ◽  
Ras Signaling ◽  
Gtpase Activating Protein ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Ras Gtpase ◽  
Acute Myeloid

Abstract Hyperactive RAS signaling is caused by mutations in RAS genes or a deficiency of the neurofibromatosis gene (NF1) and is common in myeloid malignancies. In mice, expression of oncogenic K-RAS or inactivation of Nf1 in hematopoietic cells results in myeloproliferative disorders (MPDs) that do not progress to acute myeloid leukemia (AML). Because NF1 is a RAS-GTPase–activating protein it has been proposed that NF1 deficiency is functionally equivalent to an oncogenic RAS. It is not clear, however, whether Nf1 deficiency would be redundant in K-RAS–induced MPD development or whether the 2 mutations would cooperate in leukemogenesis. Here, we show that the simultaneous inactivation of Nf1 and expression of K-RASG12D in mouse hematopoietic cells results in AML that was fatal in primary mice within 4 weeks and transplantable to sublethally irradiated secondary recipients. The data point to a strong cooperation between Nf1 deficiency and oncogenic K-RAS.

scholarly journals A Ras-GTPase-activating protein SH3-domain-binding protein.

1996 ◽  
Vol 16 (6) ◽  
pp. 2561-2569 ◽  
Author(s):  
F Parker ◽  
F Maurier ◽  
I Delumeau ◽  
M Duchesne ◽  
D Faucher ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Sh3 Domain ◽  
Ras Signaling ◽  
Gtpase Activating Protein ◽  
Ras Gtpase ◽  
Rich Domain ◽  
Acid Protein ◽  
Amino Acid Protein

We report the purification of a Ras-GTPase-activating protein (GAP)-binding protein, G3BP, a ubiquitously expressed cytosolic 68-kDa protein that coimmunoprecipitates with GAP. G3BP physically associates with the SH3 domain of GAP, which previously had been shown to be essential for Ras signaling. The G3BP cDNA revealed that G3BP is a novel 466-amino-acid protein that shares several features with heterogeneous nuclear RNA-binding proteins, including ribonucleoprotein (RNP) motifs RNP1 and RNP2, an RG-rich domain, and acidic sequences. Recombinant G3BP binds effectively to the GAP SH3 domain G3BP coimmunoprecipitates with GAP only when cells are in a proliferating state, suggesting a recruitment of a GAP-G3BP complex when Ras is in its activated conformation.

Abstract 191: Ras GTPase-activating Protein SH3 Domain Binding Protein 1 (G3BP1) Regulates The Induction Of Stress Granules During Cardiac Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Danish Sayed
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Posttranscriptional Regulation ◽  
Binding Protein ◽  
Stress Granules ◽  
Sh3 Domain ◽  
Gtpase Activating Protein ◽  
Ras Gtpase ◽  
Mrna Binding

Stress granules (SGs) are dynamic, microscopically visible, cytoplasmic bodies that play a major role in mRNA metabolism (e.g. sorting, storage, decay) and induced in cells during stress conditions like starvation, oxidative strain or growth. With substantial role in cancer and neurodegenerative diseases, these granules have never been studied during cardiac hypertrophy, or in the heart in general. Several studies have identified independent proteins, mostly mRNA binding proteins that are part of these granules, some of which are sufficient to nucleate the assembly in quiescent cells even without stress. One such mRNA binding protein is Ras GTPase-activating protein SH3 domain binding protein 1 (G3BP1), which increases during cardiac hypertrophy via posttranscriptional regulation. Thus, we hypothesized that G3BP1 might be involved in the induction of SGs during hypertrophy and hence in regulating mRNA processing and gene expression. Our aim was to investigate, 1) if these SGs appear in hypertrophied hearts and 2) if G3BP1 is necessary and sufficient to induce them during hypertrophic stimuli. In vivo staining of TIA-1/TIAR (SG marker) in mouse hearts subjected to sham or transaortic coarctation (TAC) surgeries showed accumulation of these granules with cardiac hypertrophy. Similar induction was seen in isolated, cultured, rat neonatal cardiac myocytes with hypertrophic stimulation (Endothelin1) or overexpression of G3BP1 alone (>60% of myocytes stained for SG). Conversely, switch to growth-inhibited conditions or knockdown of G3BP1 in hypertrophying myocytes was sufficient to prevent the assembly of these structures. Co-staining with other components of these granules like TIA-1/TIAR or proteins specific to P bodies, like decapping enzyme 1 validated these structures as SGs in cardiac myocytes. Interestingly, a long non-coding RNA, Gas5 (Growth Arrest Specific 5) that is validated binding partner of G3BP1 sequestered to perinuclear focal locations in myocytes stimulated with ET1, suggesting growth-induced recruitment to SGs. While we are still in process of examining G3BP1 targets that are recruited to SGs and their role in hypertrophy development, we have concluded that G3BP1 is required for the induction of SGs during cardiac hypertrophy

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