Positive and Negative Roles of p85α and p85β Regulatory Subunits of Phosphoinositide 3-Kinase in Insulin Signaling

Kohjiro Ueki, David A. Fruman, Claudine M. Yballe, Mathias Fasshauer, Johannes Klein, Tomoichiro Asano, Lewis C. Cantley, C. Ronald Kahn
2003 Journal of Biological Chemistry  
Class IA phosphoinositide (PI) 3-kinase is composed of a p110 catalytic subunit and a p85 regulatory subunit and plays a pivotal role in insulin signaling. To explore the physiological roles of two major regulatory isoforms, p85␣ and p85␤, we have established brown adipose cell lines with disruption of the Pik3r1 or Pik3r2 gene. Pik3r1 ؊/؊ (p85␣ ؊/؊ ) cells show a 70% reduction of p85 protein and a parallel reduction of p110. These cells have a 50% decrease in PI 3-kinase activity and a 30%
more » ... ease in Akt activity, leading to decreased insulininduced glucose uptake and anti-apoptosis. Pik3r2 ؊/؊ (p85␤ ؊/؊ ) cells show a 25% reduction of p85 protein but normal levels of p85-p110 and PI 3-kinase activity, supporting the fact that p85 is more abundant than p110 in wild type. p85␤ ؊/؊ cells, however, exhibit significantly increased insulin-induced Akt activation, leading to increased anti-apoptosis. Reconstitution experiments suggest that the discrepancy between PI 3-kinase activity and Akt activity is at least in part due to the p85-dependent negative regulation of downstream signaling of PI 3-kinase. Indeed, both p85␣ ؊/؊ cells and p85␤ ؊/؊ cells exhibit significantly increased insulin-induced glycogen synthase activation. p85␣ ؊/؊ cells show decreased insulin-stimulated Jun N-terminal kinase activity, which is restored by expression of p85␣, p85␤, or a p85 mutant that does not bind to p110,
doi:10.1074/jbc.m305602200 pmid:14504291 fatcat:ine7hmhi4jc65j4vlztfg76z2m