Unique and redundant roles of class IA PI3Kinase regulatory subunits in mast cell development

Mast cells are effector cells of the immune system that are derived from hematopoietic stem cells. These cells regulate both innate and adaptive immunity and have also been implicated in a variety of inflammatory diseases. The maturation of these cells is dependent on signals regulated via the c-Kit and IL-3 receptors as well as transcription factors including MITF. While the role of c-Kit and IL-3 receptor in mast development is known; the signaling molecules downstream from these receptors involved in regulating the growth and maturation of these cells are poorly understood. Class 1 A phosphatidylinositol 3-kinase (PI3K) is a lipid kinase composed of heterodimer made up of p85 regulatory subunit(s) and p110 catalytic subunit(s). In hematopoietic cells, class 1 A PI3K consists of four variants of p85 (p85α, p85β, p55α and p50α) and three variants of p110 (p110α, p110β and p110δ). While p85α, p55α and p50α are splice variants of a single gene, Pik3r1, p85β is encoded by separate gene, Pik3r2. The catalytic subunits p110α, p110β and p110δ are encoded by separate genes, Pik3ca, Pik3cb and Pik3cd, respectively. p85α and p85β share near 80% homology in the C terminus and only 40% homology in the N terminus. The shorter isoforms p55α and p50α completely lack N-terminal end sequences, including the SH3 and the BH domains of p85α. While the regulatory subunits mediate the binding and localization of the PI3K enzyme to activated cytokine or receptor tyrosine kinases; the catalytic subunits convert phosphatidylinositol4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3). In general, it is believed that regulatory subunits of class 1 A PI3K bind with equal Unique and redundant roles of class IA PI3Kinase regulatory subunits in mast cell development