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 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.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Anthony O
AO
Beas
Vanessa
V
Taupin
Carmen
C
Teodorof
Lien T
LT
Nguyen
Mikel
M
Garcia-Marcos
Marilyn G
MG
Farquhar
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002522:Chlorocebus aethiops; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C512478:EGFR protein, human; D066246:ErbB Receptors; D020962:Heterotrimeric GTP-Binding Proteins