Phosphatidylinositol 3-kinase isoforms as targets in respiratory disease

John A Marwick1, Kian Fan Chung, Ian M Adcock

  • 1Section of Airways Disease, National Heart and Lung Institute, Imperial College London, London, UK. j.marwick@imperial.ac.uk

Insights

Phosphoinositide 3-kinase (PI3K) signaling is crucial for immune responses in respiratory diseases like COPD and asthma. Targeting PI3Kgamma and PI3Kdelta may offer new therapeutic strategies for these conditions.

Area of Science:

  • Immunology
  • Pharmacology
  • Respiratory Medicine

Background:

  • Current therapies inadequately control chronic obstructive pulmonary disease (COPD), severe asthma, cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF).
  • The molecular mechanisms and pathogenesis of these respiratory diseases are not fully understood, hindering the identification of new therapeutic targets.

Purpose of the Study:

  • To investigate the role of phosphoinositide 3-kinase (PI3K) signaling in the immune system and its potential as a therapeutic target for respiratory diseases.
  • To explore the specific involvement of leukocyte-specific PI3Kgamma and PI3Kdelta isoforms in inflammatory responses.

Main Methods:

  • Review of recent studies identifying PI3K as a central signaling mediator in immune responses.
  • Focus on pharmacologically targeting leukocyte-specific PI3Kgamma and PI3Kdelta isoforms.

Main Results:

  • PI3K plays an integral role in the initiation and maintenance of inflammatory responses.
  • PI3Kgamma and PI3Kdelta are central to leukocyte function and can be targeted pharmacologically.

Conclusions:

  • Early clinical studies using selective PI3K isoform inhibitors are necessary to evaluate their therapeutic potential in respiratory diseases.
  • Targeting PI3K may help control innate and adaptive inflammatory responses, restore glucocorticoid function, and reduce tumorigenesis in respiratory conditions.

Related Concept Videos

Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
Respiratory Syncytial Virus Disease01:29

Respiratory Syncytial Virus Disease

Human respiratory syncytial virus (RSV) is a widespread pathogen that primarily targets infants and young children but also poses a serious health risk to elderly and immunocompromised individuals. Belonging to the Pneumoviridae family, RSV is a negative-sense, single-stranded RNA virus within the Pneumovirus genus. Its global health burden is significant, with millions of cases annually resulting in hospitalizations and mortality, particularly in resource-limited settings. Although most...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...