scholarly journals RAF autoinhibition and 14-3-3 proteins promote paradoxical activation

2019 ◽  
Author(s):  
Gaurav Mendiratta ◽  
Thomas McFall ◽  
Edward C. Stites
Keyword(s):  
Mathematical Modeling ◽  
Conformational Changes ◽  
Kinase Inhibitors ◽  
Experimental Methods ◽  
Third Generation ◽  
Kinase Signaling ◽  
Dynamical Equilibrium ◽  
Raf Kinase ◽  
Equilibrium Dynamics

AbstractRAF kinase inhibitors can actually increase RAF kinase signaling. This process, which is commonly referred to as “paradoxical activation” (PA), is incompletely understood. RAF kinases are regulated by autoinhibitory conformational changes, and the role of these conformational changes in PA is unclear. Our mathematical investigations find that PA can result from a dynamical equilibrium between autoinhibited and non-autoinhibited forms of RAF, along with the RAF inhibitor stabilizing the non-autoinhibited form. We also investigate whether PA is influenced by 14-3-3 proteins, which can both stabilize RAF autoinhibition and RAF dimerization. Using both computational and experimental methods we demonstrate that 14-3-3 proteins potentiate PA. Third generation RAF inhibitors normally display minimal to no PA. Our mathematical modeling led us to hypothesize that increased 14-3-3 expression should also amplify PA for these agents. Subsequent experiments support our hypothesis and show that 14-3-3 overexpression increases PA in these third generation RAF inhibitors, effectively “breaking” these “paradox breakers” and pan-RAF inhibitors. We have therefore created and experimentally validated a robust mechanism for PA based solely on equilibrium dynamics of canonical interactions in RAF signaling.

Role of spectrin in membrane fusion and in shape change of human erythrocyte ghost

1978 ◽  
Vol 36 (2) ◽  
pp. 328-329
Author(s):  
Hideo Hayashi ◽  
Yoshikazu Hirai ◽  
John T. Penniston
Keyword(s):  
Conformational Changes ◽  
Human Erythrocyte ◽  
Shape Change ◽  
Membrane Surface ◽  
Slight Modification ◽  
Active Role ◽  
Main Role ◽  
Bank Blood ◽  
Human Erythrocyte Ghost

Spectrin is a membrane associated protein most of which properties have been tentatively elucidated. A main role of the protein has been assumed to give a supporting structure to inside of the membrane. As reported previously, however, the isolated spectrin molecule underwent self assemble to form such as fibrous, meshwork, dispersed or aggregated arrangements depending upon the buffer suspended and was suggested to play an active role in the membrane conformational changes. In this study, the role of spectrin and actin was examined in terms of the molecular arrangements on the erythrocyte membrane surface with correlation to the functional states of the ghosts.Human erythrocyte ghosts were prepared from either freshly drawn or stocked bank blood by the method of Dodge et al with a slight modification as described before. Anti-spectrin antibody was raised against rabbit by injection of purified spectrin and partially purified.

The role of verbal conditioning in third generation behavior therapy.

2005 ◽  
Vol 6 (2) ◽  
pp. 137-146 ◽  
Author(s):  
Joseph Cautilli ◽  
T. Chris Riley-Tillman ◽  
Saul Axelrod ◽  
Philip Hineline
Keyword(s):  
Behavior Therapy ◽  
Third Generation ◽  
Verbal Conditioning

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

Minangkabau Language Maintenance by the Association of Sei Jaring Community in Medan

2014 ◽  
Vol 11 (2) ◽  
Author(s):  
Yenita Uswar ◽  
Amrin Saragih ◽  
Tina Mariany Arifin
Keyword(s):  
Qualitative Research ◽  
Data Analysis ◽  
Language Maintenance ◽  
Young Generation ◽  
Third Generation ◽  
The Third ◽  
Danger Level

The objectives of this qualitative research were (1) to identify the factors that affect the Minangkabau language (ML) maintenance in Medan, (2) to discover the parents’ efforts in maintaining ML in Medan and (3) to find out the reason why the speakers have to maintain ML. The souree of data is the nembers of the Association of Sei Jaring Community (Ikatan Warga Sei Jaring: IWS) in Medan. The sample was 10 families including 10 parents and their children. The instruments of this study are a questionnaire and an interview. The questionnaire was used to answer the factors affected the maintenance of ML and how factors affected the maintenance of ML. The interview was used to discover the influence why Minangkabau’s people have to maintain ML. There are four factors in ML maintenance, the parents’ role, the role of family, the intramarriage and homeland visits. After distributing questionnaire and did some interviews it is found that IWS especially for the third generation (children) has the danger level in ML when they communicate to each other. Meanwhile, the data analysis also shows that both fathers and mothers communicate to each other with ML. This condition occurred because of the influence of the environment. Parents have to keep communication and teaching Minangkabau language continuously to their children. so, the young generation can keep the existence of ML for their future. Keywords: Minangkabau Language Maintenance, parents’ efforts, the young generation.

Technique of scientific and technical forecasting using neural networks

2018 ◽  
pp. 103-110
Author(s):  
V. V. Nefedev
Keyword(s):  
Mathematical Modeling ◽  
Neural Networks ◽  
Artificial Neural Networks ◽  
Original Method ◽  
Forecasting Methods ◽  
Expert Assessments ◽  
Artificial Neural

For the definition and implementation of breakthrough technologies the most important is the role of scientific and technical forecasting. Well-known forecasting methods based on extrapolation, expert assessments and mathematical modeling are not universal and have a number of significant disadvantages. The article proposes an original method of scientific and technical forecasting based on the use of the methodology of artificial neural networks. 

Pharmacophore and Binding Analysis of Known and Novel B-RAF Kinase Inhibitors

2014 ◽  
Vol 21 (17) ◽  
pp. 1938-1955 ◽  
Author(s):  
F. Baska ◽  
I. Szabadkai ◽  
A. Sipos ◽  
N. Breza ◽  
C. Szantai-Kis ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Raf Kinase ◽  
Binding Analysis
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