Editors' ChoiceCell Biology

MAPping PI3K signaling to endosomes

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Science Signaling  17 Nov 2020:
Vol. 13, Issue 658, eabf7090
DOI: 10.1126/scisignal.abf7090

The microtubule-associated protein MAP4 recruits PI3Kα from the plasma membrane to endosomes to activate Akt signaling.

Upon stimulation of cell surface receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), type IA phosphoinositide 3-kinases (PI3Ks) are recruited to activated receptors and convert the membrane phospholipid PIP2 to PIP3. The kinase Akt is then recruited to the plasma membrane where it is activated. PI3K-Akt signaling is critical for cell proliferation, and hyperactivation of this pathway is associated with many cancers. Through fluorescence microscopy studies, Western blotting analysis, and protein-protein interaction experiments, Thapa et al. provide an alternative mechanism for the PI3Kα-mediated generation of PIP3 and activation of Akt. In EGF-stimulated cell lines, PIP3 and activated Akt accumulated on intracellular membranes and PI3Kα was recruited to endosomal vesicles along microtubules. Mass spectrometry analysis revealed the microtubule-binding protein MAP4 as a PI3Kα binding partner. This interaction occurred between the microtubule-binding domain (MTBD) of MAP4 and the C2 domain of the p110α catalytic subunit of PI3Kα. Loss of MAP4 disrupted the interaction of PI3Kα with stimulated EGFRs without affecting EGFR activation and prevented PI3Kα localization to microtubules. Knockdown of MAP4 also prevented the EGF-stimulated accumulation of PIP3 on endosomal membranes. Finally, loss of MAP4 impaired the activation of Akt at endosomal membranes, which was rescued by ectopic expression of wild-type MAP4 but not of a mutant MAP4 lacking the MTBD. As discussed in commentary by Batrouni and Baskin, further studies are needed to determine the source of PIP2 at endosomes; however, these findings suggest that MAP4 is a potential therapeutic target to disrupt the PI3Kα-Akt signaling pathway in cancers.

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