#pi3k

Well Packed

You probably wear the jeans that are in easy reach at the top of your overstuffed drawers more than those tucked at the back. Some genes, too, are easier to reach than others. Genetic material is tightly packed into a structure called chromatin, and which genes are expressed can depend on how this packing unfurls. Researchers hoping to understand how these structural changes guide the development of our lungs compared gene activity to packing structure in mouse lung starter cells (pictured) that produce a protein called Sox9 (red). They identified the proteins responsible for chromatin reshaping, and key signalling pathways vital to healthy lung development. Mice with a particular molecular pathway blocked failed to produce healthy lung linings and developed defective lungs. This knowledge could lead to explanations of how some developmental lung diseases take hold, and perhaps even reveal which existing treatments could be repurposed for other conditions.

Written by Anthony Lewis

Image from work by Divya Khattar and Sharlene Fernandes, and colleagues

Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA

Image originally published with a Creative Commons Attribution 4.0 International (CC BY 4.0)

Published in eLife, August 2022

Xing Tan, Pei-Lei Jiao, Yang-Kai Wang, Zhao-Tang Wu, Xiao-Rong Zeng, Miao-Ling Li, Wei-Zhong Wang

Neuroinflammation  is associated with cardiovascular dysfunction. The purpose of this study is to  determine the role of the PI3K signaling in neuroinflammation in the RVLM of  hypertension.

For this  purpose 16 weeks old Spontaneously Hypertensive rats (SHR) and Wistar Kyoto  rats (WKY) were used.  Gene silencing  of PI3K in the RVLM attenuated the levels of neuroinflammation and  cardiovascular function in SHR.

Silencing of  PI3K in the RVLM inhibited the cardiovascular excitation and neuroinflammation  induced by central Ang II

ACE2  overexpression in the RVLM attenuated the increased neuroinflammation,  cardiovascular excitation, and upregulation of PI3K/AKT signaling in the  LPS-induced hypertensive rats and SHR.

Taken  together, these findings indicate that the PI3K signaling in the RVLM is involved in the pathogenesis of neuroinflammation in hypertension. It is also suggested that inactivation of the PI3K signaling mediates the antineuroinflammation effect of ACE2 overexpression in the RVLM in hypertensive rats.

All these  results suggest that both neuroinflammation and cardiovascular excitation  induced by central infusion of Ang II are prevented by pretreatment with RVLM  PI3K knockdown.

Mahesh Kumar Sivasubramanian

You get PIP3 by phosphorylating hydroxyl groups in phosphatidylinositol. 

PI = Phosphatidylinositol (which has hydroxyls)

PI3K = Phosphatidylinositol 3 Kinase (which phosphorylates PI at position 3)

(There are also PI4K and PI5K, which do the same thing--phosphorylate the hydroxyls in phosphatidylinositol--except at positions 4 and 5, respectively, to give you phosphatidylinositol-3,4,5-triphosphate)

PIP2 = phosphatidylinositol-4,5-bisphosphate

TNFRSF binding is generally held to signal through NFkB pathways - but in many cases have been shown to increase pAKT and/or have effects negated through inhibition of PI3K/AKT.

General principles: TNFRSF need to cluster/oligomerise to signal. - soluble ligand trimers tend not to signal well unless artificially oligomerised or unless receptors are pre-clustered. - clustering = translocation into detergent-insoluble membrane (DIM) compartments, mediated by TRAF2 --> both translocation and TRAF2 required for signalling (studied in OX40). - PIP2 enriched in DIM; in T cells some fraction of PI3K/PDK1 constitutively associate with DIM. - Formation of ‘signallosome’ in DIM: (OX40) TRAF2, IKK, CARMA1-BCL10-MALTI1 (NFkB machinery), PKC-theta, p85-PI3K/AKT***. *** TCR signalling not required for inclusion but required for activation - regulatory measures specific to T cells; role in bringing PI3K close to TCR/CD28 signallosome?

EXAMPLES

TNFR2 (ligand TNF) - sustains pAKT following TCR/CD28 stimulation. - favours Teff development over iTreg differentiation? TNFa neutralisation reduces iTreg; pAKT associates with Smad3/inhibits TGFb-driven Foxp3 transcription.

OX40 (ligand OX40L) - AKT loss of function resembles OX40KO; constitutively active AKT rescues OX40 deficiency. - also antagonises iTreg differentiation.

4-1BB (ligand 4-1BBL) - enhances T cell proliferation, antagonised by AKT inhibition. - directly or indirectly enhances IFNg production --> inhibits iTreg differntiation.

HVEM (ligand LIGHT) - deletion reduces AKT activity --> reduces T cell survival --> rescued by constitutive AKT activity.

DR3 (ligand TL1A) (autocrine signalling in activated T cells) - observed to be highly expressed on Tregs and not Tcon in allergic lung inflammation (mouse asthma), agonist antibody 4C12 selectively enhances Treg proliferation, blocked by AKT inhibition https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947231/ - TL1A-expressing tumours elicit strong CD8 response https://www.ncbi.nlm.nih.gov/pubmed/21688261 - Sustained TL1A expression in DCs triggers intestinal goblet hyperplasia, increases Treg turnover but decreases suppressive function https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053556/ - Other examples of high TL1A in autoimmune settings, blocking reduces severity; equal expression on Tregs and activated Tcons; enhancement of Th1/Th2 responses; inhibition of iTreg differentiation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763597/?report=classic#B65

Fig 2.

Mutations in RAS genes

Mutations in RAS genes

Larry H Bernstein, MD, FCAP, Curator

LPBI

  Novel Mechanism Targets “Undruggable” RAS Oncogenes

http://www.genengnews.com/gen-news-highlights/novel-mechanism-targets-undruggable-ras-oncogenes/81252643/

https://youtu.be/PUOKny18iro

Dr. Reddy discussing findings from new research on developing drugs toward RAS.

http://www.genengnews.com/Media/images/GENHighlight/fx1118515712…

New mTOR inhibitor from Exelixis, Inc.,

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone  [7-​(6-​amino-​3-​pyridinyl)​-​2,​3-​dihydro-​1,​4-​benzoxazepin-​4(5H)​-​yl]​[3-​fluoro-​2-​methyl-​4-​(methylsulfonyl)​phenyl]​-Methanone, (7-(6-Aminopyridin-3-yl)-2,3-dihydrobenz[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone MW 455.50,…

Spanish Team Develops Anti-Obesity Treatment in Animal Models

A research team from the Spanish National Cancer Research Center (CNIO) has shown that partial pharmacological inhibition of the PI3K enzyme in obese mice and monkeys reduces body weight and physiological manifestations of metabolic syndrome, specifically diabetes and hepatic steatosis (fatty liver disease), without any signs of side effects or toxicities. They published their work in the journal…

Activation of PI3Kalpha by Physiological Effectors and by Oncogenic