Enhanced PI3K/Akt Signaling in Response to p85α Loss is Regulated by Endosomal PI3Kα and PI3P

Abstract

PI3K is a heterodimer of p110 catalytic subunit and p85 adaptor subunit that is activated by agonist-stimulated receptor tyrosine kinases. Although the interaction of p85 with activated receptors recruits p110 to membranes, studies have demonstrated that p85 loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. We recently demonstrated that p110 localizes to microtubules via MAP4, facilitating its interaction with activated receptor kinases in endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85 knock down the residual p110, coupled predominantly to p85{beta}, exhibits enhanced microtubule localization, MAP4 binding and interaction with endosomal receptor tyrosine kinases, thereby augmenting PI3K/Akt signaling. The interaction of the C2 domain of p110 with PI3P is required for recruiting p110 into endomembranes and enhancing PI3K/Akt signaling. These findings provide a mechanism for the augmented agonist-stimulated PI3K/Akt signaling upon p85 loss and point to novel therapeutic targets for cancer. IN BRIEFThis study provides the comprehensive mechanism for p85 loss induced and receptor tyrosine kinase stimulated PI3K/Akt signaling.