Adaptor protein containing PH domain, PTB domain and leucine zipper (APPL1) regulates the protein level of EGFR by modulating its trafficking.
The EGFR-mediated signaling pathway regulates multiple biological processes such as cell proliferation, survival and differentiation. Previously APPL1 (adaptor protein containing PH domain, PTB domain and leucine zipper 1) has been reported to function as a downstream effector of EGF-initiated signaling. Here we demonstrate that APPL1 regulates EGFR protein levels in response to EGF stimulation. Overexpression of APPL1 enhances EGFR stabilization while APPL1 depletion by siRNA reduces EGFR protein levels. APPL1 depletion accelerates EGFR internalization and movement of EGF/EGFR from cell surface to the perinuclear region in response to EGF treatment. Conversely, overexpression of APPL1 decelerates EGFR internalization and translocation of EGF/EGFR to the perinuclear region. Furthermore, APPL1 depletion enhances the activity of Rab5 which is involved in internalization and trafficking of EGFR and inhibition of Rab5 in APPL1-depleted cells restored EGFR levels. Consistently, APPL1 depletion reduced activation of Akt, the downstream signaling effector of EGFR and this is restored by inhibition of Rab5. These findings suggest that APPL1 is required for EGFR signaling by regulation of EGFR stabilities through inhibition of Rab5.
Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea.
Jae-Rin
JR
Lee
Hwa-Sun
HS
Hahn
Young-Hoon
YH
Kim
Hong-Hoa
HH
Nguyen
Jun-Mo
JM
Yang
Jong-Sun
JS
Kang
Myong-Joon
MJ
Hahn
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D020696:rab5 GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D034741:RNA, Small Interfering; C512478:EGFR protein, human; D066246:ErbB Receptors; D020696:rab5 GTP-Binding Proteins