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

Narendra Thapa, Mo Chen, Hudson T. Horn, Suyong Choi, Tianmu Wen, Richard A. Anderson

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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 PI3Kα to microtubules. The microtubule-binding domain of MAP4 binds directly to the C2 domain of the p110α catalytic subunit. MAP4 controls the interaction of PI3Kα with activated receptors at endosomal compartments along microtubules. Loss of MAP4 results in the loss of PI3Kα targeting and loss of PI3K–Akt signalling downstream of multiple agonists. The MAP4–PI3Kα assembly defines a mechanism for spatial control of agonist-stimulated PI3K–Akt signalling at internal membrane compartments linked to the microtubule network.

Original languageEnglish (US)
Pages (from-to)1357-1370
Number of pages14
JournalNature Cell Biology
Volume22
Issue number11
DOIs
StatePublished - Nov 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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