Novel Tumor Suppressive Role of the RAS GTPase-Activating Protein RASA5 to RAS Signaling Perturbation in Human Carcinomas

2019 ◽  
Author(s):  
Lili Li ◽  
Yichao Fan ◽  
Xin Huang ◽  
Lan Zhong ◽  
Xing-sheng Shu ◽  
...  
Keyword(s):  
Ras Signaling ◽  
Gtpase Activating Protein ◽  
Ras Gtpase ◽  
Human Carcinomas

Domain topology of human Rasal

2017 ◽  
Vol 399 (1) ◽  
pp. 63-72 ◽  
Author(s):  
Jorge Cuellar ◽  
José María Valpuesta ◽  
Alfred Wittinghofer ◽  
Begoña Sot
Keyword(s):  
Electron Microscopy ◽  
Small Gtpase ◽  
Full Length ◽  
Gtpase Activating Protein ◽  
Ras Gtpase ◽  
Cryo Electron Microscopy ◽  
Domain Protein ◽  
Negative Staining Electron Microscopy ◽  
Resolution Structure

AbstractRasal is a modular multi-domain protein of the GTPase-activating protein 1 (GAP1) family; its four known members, GAP1m, Rasal, GAP1IP4BPand Capri, have a Ras GTPase-activating domain (RasGAP). This domain supports the intrinsically slow GTPase activity of Ras by actively participating in the catalytic reaction. In the case of Rasal, GAP1IP4BPand Capri, their remaining domains are responsible for converting the RasGAP domains into dual Ras- and Rap-GAPs, via an incompletely understood mechanism. Although Rap proteins are small GTPase homologues of Ras, their catalytic residues are distinct, which reinforces the importance of determining the structure of full-length GAP1 family proteins. To date, these proteins have not been crystallized, and their size is not adequate for nuclear magnetic resonance (NMR) or for high-resolution cryo-electron microscopy (cryoEM). Here we present the low resolution structure of full-length Rasal, obtained by negative staining electron microscopy, which allows us to propose a model of its domain topology. These results help to understand the role of the different domains in controlling the dual GAP activity of GAP1 family proteins.

scholarly journals The chemotactic response to PDGF-BB: evidence of a role for Ras.

1995 ◽  
Vol 130 (3) ◽  
pp. 725-731 ◽  
Author(s):  
V Kundra ◽  
B Anand-Apte ◽  
L A Feig ◽  
B R Zetter
Keyword(s):  
Chemotactic Response ◽  
Dominant Negative ◽  
Pdgf Receptor ◽  
Gtpase Activating Protein ◽  
Ras Gtpase ◽  
Downstream Effector ◽  
Ras Inhibition ◽  
Receptor Beta ◽  
Constitutively Active

The PDGF receptor-beta mediates both mitogenic and chemotactic responses to PDGF-BB. Although the role of Ras in tyrosine kinase-mediated mitogenesis has been characterized extensively, its role in PDGF-stimulated chemotaxis has not been defined. Using cells expressing a dominant-negative ras, we find that Ras inhibition suppresses migration toward PDGF-BB. Overexpression of either Ras-GTPase activating protein (Ras-GAP) or a Ras guanine releasing factor (GRF) also inhibited PDGF-stimulated chemotaxis. In addition, cells producing excess constitutively active Ras failed to migrate toward PDGF-BB, consistent with the observation that either excess ligand or excess signaling intermediate can suppress the chemotactic response. These results suggest that Ras can function in normal cells to support chemotaxis toward PDGF-BB and that either too little or too much Ras activity can abrogate the chemotactic response. In contrast to Ras overexpression, cells producing excess constitutively active Raf, a downstream effector of Ras, did migrate toward PDGF-BB. Cells expressing dominant-negative Ras were able to migrate toward soluble fibronectin demonstrating that these cells retained the ability to migrate. These results suggest that Ras is an intermediate in PDGF-stimulated chemotaxis but may not be required for fibronectin-stimulated cell motility.

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.

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

The Role of ras GTPase Activating Protein in Human Tumorigenesis

Pathobiology ◽  
1995 ◽  
Vol 63 (6) ◽  
pp. 348-350 ◽  
Author(s):  
Eitan Friedman
Keyword(s):  
Gtpase Activating Protein ◽  
Ras Gtpase

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.

A Molecular Approach to Immunoscintigraphy: A Study of the T-Antigen Conformation on the Surface of Tumors

1987 ◽  
Vol 26 (01) ◽  
pp. 1-6 ◽  
Author(s):  
S. Selvaraj ◽  
M. R. Suresh ◽  
G. McLean ◽  
D. Willans ◽  
C. Turner ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cell ◽  
T Antigen ◽  
Human Carcinomas ◽  
Animal Tumor ◽  
Synthetic Antigens

The role of glycoconjugates in tumor cell differentiation has been well documented. We have examined the expression of the two anomers of the Thomsen-Friedenreich antigen on the surface of human, canine and murine tumor cell membranes both in vitro and in vivo. This has been accomplished through the synthesis of the disaccharide terminal residues in both a and ß configuration. Both entities were used to generate murine monoclonal antibodies which recognized the carbohydrate determinants. The determination of fine specificities of these antibodies was effected by means of cellular uptake, immunohistopathology and immunoscintigraphy. Examination of pathological specimens of human and canine tumor tissue indicated that the expressed antigen was in the β configuration. More than 89% of all human carcinomas tested expressed the antigen in the above anomeric form. The combination of synthetic antigens and monoclonal antibodies raised specifically against them provide us with invaluable tools for the study of tumor marker expression in humans and their respective animal tumor models.

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