Phosphatidylinositol-3-OH kinase signalling is spatially organized at endosomal compartments by microtubule-associated protein 4

Intracellularly regulated PI3K activation. Thapa et al. find that phosphatidylinositol-3,4,5-trisphosphate generation and Akt activation occur at intracellular membranes, rather than the plasma membrane, and that this is mediated by MAP4, which controls PI3K alpha localization to microtubules. The canonical model of agonist-stimulated phosphatidylinositol-3-OH kinase (PI3K)-Akt signalling proposes that PI3K is activated at the plasma membrane, where receptors are activated and phosphatidylinositol-4,5-bisphosphate is concentrated. Here we show that phosphatidylinositol-3,4,5-trisphosphate generation and activated Akt are instead largely confined to intracellular membranes upon receptor tyrosine kinase activation. Microtubule-associated protein 4 (MAP4) interacts with and controls localization of membrane vesicle-associated PI3K alpha to microtubules. The microtubule-binding domain of MAP4 binds directly to the C2 domain of the p110 alpha catalytic subunit. MAP4 controls the interaction of PI3K alpha with activated receptors at endosomal compartments along microtubules. Loss of MAP4 results in the loss of PI3K alpha targeting and loss of PI3K-Akt signalling downstream of multiple agonists. The MAP4-PI3K alpha assembly defines a mechanism for spatial control of agonist-stimulated PI3K-Akt signalling at internal membrane compartments linked to the microtubule network.