title: AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve.
abstract: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that controls cell proliferation, growth, survival, metabolism, and migration by activating the PI3K (phosphatidylinositol 3-kinase)-AKT and ERK (extracellular signal-regulated kinase)-RSK (ribosomal S6 kinase) pathways. EGFR signaling to these pathways is temporally and spatially regulated. Endocytic trafficking controls the access of EGFR to these downstream effectors and also its degradation, which terminates EGFR signaling. We showed that AKT facilitated the endocytic trafficking of EGFR to promote its degradation. Interfering with AKT signaling reduced both EGFR recycling and the rate of EGFR degradation. In AKT-impaired cells, EGFRs were unable to reach the cell surface or the lysosomal compartment and accumulated in the early endosomes, resulting in prolonged signaling and increased activation of ERK and RSK. Upon EGF stimulation, AKT phosphorylated and activated the kinase PIKfyve [FYVE-containing phosphatidylinositol 3-phosphate 5-kinase], which promoted vesicle trafficking to lysosomes. PIKfyve activation promoted EGFR degradation. Similar regulation occurred with platelet-derived growth factor receptor (PDGFR), suggesting that AKT phosphorylation and activation of PIKfyve is likely to be a common feedback mechanism for terminating RTK signaling and reducing receptor abundance.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ekrem Emrah
authors.initials: EE
authors.lastname: Er
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Mendoza
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Mackey
authors.forename: Lucia E
authors.initials: LE
authors.lastname: Rameh
authors.forename: John
authors.initials: J
authors.lastname: Blenis
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D018613:Microscopy, Confocal; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C492139:PIKFYVE protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt