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Crosstalk between Akt/ GSK 3β signaling and dynamin‐1 regulates clathrin‐mediated endocytosis
Author(s) -
Reis Carlos R,
Chen PingHung,
Srinivasan Saipraveen,
Aguet François,
Mettlen Marcel,
Schmid Sandra L
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201591518
Subject(s) - biology , endocytosis , dynamin , crosstalk , microbiology and biotechnology , clathrin , signal transducing adaptor protein , protein kinase b , phosphorylation , signal transduction , receptor , genetics , physics , optics
Clathrin‐mediated endocytosis ( CME ) regulates signaling from the plasma membrane. Analysis of clathrin‐coated pit ( CCP ) dynamics led us to propose the existence of a rate‐limiting, regulatory step(s) that monitor the fidelity of early stages in CCP maturation. Here we show that nascent endocytic vesicles formed in mutant cells displaying rapid, dysregulated CME are defective in early endosomal trafficking, maturation and acidification, confirming the importance of this “checkpoint.” Dysregulated CME also alters EGF receptor signaling and leads to constitutive activation of the protein kinase Akt. Dynamin‐1, which was thought to be neuron specific, is activated by the Akt/ GSK 3β signaling cascade in non‐neuronal cells to trigger rapid, dysregulated CME . Acute activation of dynamin‐1 in RPE cells by inhibition of GSK 3β accelerates CME , alters CCP dynamics and, unexpectedly, increases the rate of CCP initiation. CRISPR ‐Cas9n‐mediated knockout and reconstitution studies establish that dynamin‐1 is activated by Akt/ GSK 3β signaling in H1299 non‐small lung cancer cells. These findings provide direct evidence for an isoform‐specific role for dynamin in regulating CME and reveal a feed‐forward pathway that could link signaling from cell surface receptors to the regulation of CME .