Simulation of the regulation of EGFR endocytosis and EGFR-ERK signaling by endophilin-mediated RhoA-EGFR crosstalk.
Deregulations of EGFR endocytosis in EGFR-ERK signaling are known to cause cancers and developmental disorders. Mutations that impaired c-Cbl-EGFR association delay EGFR endocytosis and produce higher mitogenic signals in lung cancer. ROCK, an effector of small GTPase RhoA was shown to negatively regulate EGFR endocytosis via endophilin A1. A mathematical model was developed to study how RhoA and ROCK regulate EGFR endocytosis. Our study suggested that over-expressing RhoA as well as ROCK prolonged ERK activation partly by reducing EGFR endocytosis. Overall, our study hypothesized an alternative role of RhoA in tumorigenesis in addition to its regulation of cytoskeleton and cell motility.
Ung
Choong Yong
CY
Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, 3 Science Drive 2, Singapore 117543, Singapore.
Li
Hu
H
Ma
Xiao Hua
XH
Jia
Jia
J
Li
Bao Wen
BW
Low
Boon Chuan
BC
Chen
Yu Zong
YZ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003198:Computer Simulation; D004705:Endocytosis; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C107640:SH3GL2 protein, human; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein