Pik3r1, also known as p85α, is a regulatory subunit of phosphoinositide 3-kinases (PI3Ks). PI3K, a heterodimer of a regulatory and a catalytic subunit, phosphorylates phosphatidylinositol into secondary signaling molecules involved in regulating metabolic homeostasis. Pik3r1 stabilizes and inhibits p110 catalytic activity, and acts as an adaptor to interact with insulin receptor substrate proteins and growth factor receptors. Mutations or altered expression of Pik3r1 can modulate PI3K activity, with significant metabolic outcomes. Additionally, it has been found to have PI3K-independent functions [1].

In the context of disease, heterozygous loss-of-function (LOF) mutations in Pik3r1 cause activated PI3Kδ syndrome 2 (APDS2). By studying a Nuclease technology mouse model and patients' immune cells, it was determined that Pik3r1 LOF mutations lead to decreased intrinsic B cell class switching, defective Tfh cell function, defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups [2]. Somatic activating variants in Pik3r1 cause vascular malformations with and without overgrowth, and the phenotypic features overlap with those of the PIK3CA-related overgrowth spectrum (PROS) [3].

In conclusion, Pik3r1 is crucial for regulating the activity of PI3K, which is involved in multiple biological processes. Model-based research, especially the use of KO/CKO mouse models, has revealed its role in immune-related diseases like APDS2 and in vascular malformations and overgrowth conditions. Understanding Pik3r1's functions provides insights into the mechanisms of these diseases and may guide the development of targeted therapies.