Physiological Dysfunctions Associated with Mutations of the Imprinted Gnas Locus

Physiology ◽  
2008 ◽  
Vol 23 (4) ◽  
pp. 221-229 ◽  
Author(s):  
Stefan Krechowec ◽  
Antonius Plagge
Keyword(s):  
Signal Transduction ◽  
Mouse Models ◽  
Genomic Organization ◽  
Receptor Activation ◽  
Deficient Mouse ◽  
Protein Coding ◽  
Alternative Protein ◽  
Stimulatory G Protein ◽  
Protein Variants ◽  
Complex Arrangement

The ubiquitous Gαs-subunit of the trimeric, stimulatory G-protein plays a central role in receptor-mediated signal transduction, coupling receptor activation with the production of cAMP. The Gαs-encoding locus Gnas is now known to consist of a complex arrangement of several protein-coding and noncoding transcripts. We provide an overview of its genomic organization, its regulation by genomic imprinting, and a summary of the physiological roles of the alternative protein variants Gαs and XLαs as determined from deficient mouse models.

Hepatocyte Growth Factor and Macrophage-stimulating Protein “Hinge” Analogs to Treat Pancreatic Cancer

2019 ◽  
Vol 19 (10) ◽  
pp. 782-795
Author(s):  
John W. Wright ◽  
Kevin J. Church ◽  
Joseph W. Harding
Keyword(s):  
Pancreatic Cancer ◽  
Signal Transduction ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tumor Growth ◽  
Receptor Activation ◽  
Signal Transduction Pathways ◽  
Met Receptor ◽  
Macrophage Stimulating Protein ◽  
Hepatocyte Growth

Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the “hinge regions” of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model.

scholarly journals Mapping of a Yeast G Protein βγ Signaling Interaction

Genetics ◽  
1998 ◽  
Vol 150 (4) ◽  
pp. 1407-1417 ◽  
Author(s):  
Simon J Dowell ◽  
Anne L Bishop ◽  
Susan L Dyos ◽  
Andrew J Brown ◽  
Malcolm S Whiteway
Keyword(s):  
Signal Transduction ◽  
Map Kinase ◽  
G Protein ◽  
Coiled Coil ◽  
Receptor Activation ◽  
Temperature Sensitive ◽  
Hydrophobic Residues ◽  
Map Kinase Cascade ◽  
Kinase Cascade

Abstract The mating pathway of Saccharomyces cerevisiae is widely used as a model system for G protein-coupled receptor-mediated signal transduction. Following receptor activation by the binding of mating pheromones, G protein βγ subunits transmit the signal to a MAP kinase cascade, which involves interaction of Gβ (Ste4p) with the MAP kinase scaffold protein Ste5p. Here, we identify residues in Ste4p required for the interaction with Ste5p. These residues define a new signaling interface close to the Ste20p binding site within the Gβγ coiled-coil. Ste4p mutants defective in the Ste5p interaction interact efficiently with Gpa1p (Gα) and Ste18p (Gγ) but cannot function in signal transduction because cells expressing these mutants are sterile. Ste4 L65S is temperature-sensitive for its interaction with Ste5p, and also for signaling. We have identified a Ste5p mutant (L196A) that displays a synthetic interaction defect with Ste4 L65S, providing strong evidence that Ste4p and Ste5p interact directly in vivo through an interface that involves hydrophobic residues. The correlation between disruption of the Ste4p-Ste5p interaction and sterility confirms the importance of this interaction in signal transduction. Identification of the Gβγ coiled-coil in Ste5p binding may set a precedent for Gβγ-effector interactions in more complex organisms.

Lipid signal transduction pathways in angiotensin II type 1 receptor-transfected fibroblasts

1995 ◽  
Vol 269 (2) ◽  
pp. C435-C442 ◽  
Author(s):  
Y. Wen ◽  
M. C. Cabot ◽  
E. Clauser ◽  
S. L. Bursten ◽  
J. L. Nadler
Keyword(s):  
Signal Transduction ◽  
Angiotensin Ii ◽  
Chinese Hamster ◽  
Receptor Activation ◽  
Signal Transduction Pathways ◽  
Ang Ii ◽  
Vascular Type ◽  
Lipid Signal ◽  
Fibroblast Line

A stable Chinese hamster ovary fibroblast line expressing the rat vascular type 1a angiotensin II (ANG II) receptor was used to study the lipid-derived signal transduction pathways elicited by type 1a ANG II receptor activation. ANG II caused a biphasic and dose-dependent increase in diacylglycerol (DAG) accumulation with an initial peak at 15 s (181 +/- 11% of control, P < 0.02) and a second sustained peak at 5-10 min (214 +/- 10% of control, P < 0.02). The late DAG peak was derived from phosphatidylcholine (PC), and the formation was blocked by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. ANG II also increased phosphatidic acid (PA) production nearly fourfold by 7.5 min. In the presence of ethanol, ANG II markedly increased phosphatidylethanol (PEt) formation, indicating activation of phospholipase D (PLD). ANG II was shown to increase the mass of three separate PA species, one of which apparently originated from DAG kinase action on PC-phospholipase C (PLC)-produced DAG, providing evidence for PC-PLC activity. ANG II also formed a third PA species, which originated neither from PLD nor from DAG kinase. These results demonstrate that multiple lipid signals propagated via collateral stimulation of PLC and PLD are generated by specific activation of the vascular type 1a ANG II receptor.

scholarly journals Pathophysiological Role of Autophagy: Lesson from Autophagy-Deficient Mouse Models

2011 ◽  
Vol 60 (4) ◽  
pp. 329-345 ◽  
Author(s):  
Yoshinobu ICHIMURA ◽  
Masaaki KOMATSU
Keyword(s):  
Mouse Models ◽  
Deficient Mouse ◽  
Pathophysiological Role

scholarly journals Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models

2021 ◽  
Vol 22 (9) ◽  
pp. 4778
Author(s):  
Mark Joseph Maranan Desamero ◽  
Soo-Hyun Chung ◽  
Shigeru Kakuta
Keyword(s):  
Mouse Models ◽  
Deficient Mouse ◽  
Beta Glucan ◽  
Downstream Signaling ◽  
Beta Glucans ◽  
Fungal Immunity ◽  
Anti Fungal ◽  
Susceptibility And Resistance ◽  
Deficient Mice

Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been greatly augmented through the utility of various beta-glucan cognate receptor-deficient mouse models. Analysis of dectin-1 knockout mice has clarified the downstream signaling pathways and adaptive effector responses triggered by beta-glucan in anti-fungal immunity. On the other hand, assessment of CR3-deficient mice has elucidated the compelling action of beta-glucans in neutrophil-mediated fungal clearance, and the investigation of EphA2-deficient mice has highlighted its novel involvement in host sensing and defense to oral mucosal fungal infection. Based on these accounts, this review focuses on the recent discoveries made by these gene-targeted mice in beta-glucan research with particular emphasis on the multifaceted aspects of fungal immunity.

Sign in / Sign up

Export Citation Format

Share Document