Gαs promotes EEA1 endosome maturation and shuts down proliferative signaling through interaction with GIV (Girdin)

The organization of the endocytic system into biochemically distinct subcompartments allows for spatial and temporal control of the strength and duration of signaling. Recent work has established that Akt cell survival signaling via the epidermal growth factor receptor (EGFR) occurs from APPL early...

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Bibliographic Details
Published in:Molecular biology of the cell 2012-12, Vol.23 (23), p.4623-4634
Main Authors: Beas, Anthony O, Taupin, Vanessa, Teodorof, Carmen, Nguyen, Lien T, Garcia-Marcos, Mikel, Farquhar, Marilyn G
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
Cell Proliferation
Cell Transformation, Neoplastic
Cercopithecus aethiops
COS Cells
Endosomes - metabolism
Endosomes - ultrastructure
HeLa Cells
Heterotrimeric GTP-Binding Proteins - metabolism
Humans
Microfilament Proteins - genetics
Microfilament Proteins - metabolism
Receptor, Epidermal Growth Factor - genetics
Receptor, Epidermal Growth Factor - metabolism
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Signal Transduction
Vesicular Transport Proteins - genetics
Vesicular Transport Proteins - metabolism
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Summary:The organization of the endocytic system into biochemically distinct subcompartments allows for spatial and temporal control of the strength and duration of signaling. Recent work has established that Akt cell survival signaling via the epidermal growth factor receptor (EGFR) occurs from APPL early endosomes that mature into early EEA1 endosomes. Less is known about receptor signaling from EEA1 endosomes. We show here that EGF-induced, proliferative signaling occurs from EEA1 endosomes and is regulated by the heterotrimeric G protein Gαs through interaction with the signal transducing protein GIV (also known as Girdin). When Gαs or GIV is depleted, activated EGFR and its adaptors accumulate in EEA1 endosomes, and EGFR signaling is prolonged, EGFR down-regulation is delayed, and cell proliferation is greatly enhanced. Our findings define EEA1 endosomes as major sites for proliferative signaling and establish that Gαs and GIV regulate EEA1 but not APPL endosome maturation and determine the duration and strength of proliferative signaling from this compartment.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E12-02-0133