Phosphoinositide 3-Kinase in Asthma: Novel Roles and Therapeutic Approaches

Abstract

Asthma manifests as airway hyperresponsiveness and inflammation, including coughing, wheezing, and shortness of breath. Immune cells and airway structural cells orchestrate asthma pathophysiology, leading to mucus secretion, airway narrowing, and obstruction. Phosphoinositide 3-kinase, a lipid kinase, plays a crucial role in many of the cellular and molecular mechanisms driving asthma pathophysiology and represents an attractive therapeutic target. Here, we summarize the diverse roles of phosphoinositide 3-kinase in the pathogenesis of asthma and discuss novel therapeutic approaches to treatment.

Keywords: asthma; bronchodilator; inflammation; phosphoinositide 3-kinase.

Figure 1.

Class I phosphoinositide 3-kinase (PI3K) signaling. Class I PI3Ks are activated upon agonist binding to receptor tyrosine kinases (RTK) or G protein–coupled receptors (GPCRs). RTKs will recruit PI3Ks to phosphorylated tyrosine residues, resulting in activation of PI3Ks. GPCRs can activate PI3Ks via G proteins, such as Gα or Gβγ, and through β-arrestins. PI3K phosphorylates the D-3 position of the plasma membrane lipid phosphatidylinositol-4-5-bisphosphate (PI[4,5]P₂), generating PI(3,4,5)P₃. PI(3,4,5)P₃ will recruit proteins with pleckstrin homology domains, which include phosphoinositide-dependent kinase (PDK) 1, AKT kinase (AKT), guanine exchange factors (GEFs), GTPase accelerating proteins (GAPs), Tec family kinases, and nonreceptor tyrosine kinases. These signaling proteins will subsequently affect cellular functions, including proliferation, gene expression, antiapoptosis, cytoskeletal rearrangement, and degranulation. PTEN, phosphatase and tensin homolog.

Figure 2.

Functions of class I PI3K isoforms in cells mediating asthma pathophysiology. A schematic representation of the roles of class I PI3K isoforms in various cell types involved in asthma pathophysiology. Th1, T-helper cell type 1; Th2, T-helper cell type 2.