title: Differential regulation of transcription factors by location-specific EGF receptor signaling via a spatio-temporal interplay of ERK activation.
abstract: It is well established that EGFR signals from both the plasma membrane (PM) and endosome (EN). However, very little is known about whether and how the EGFR signals at the PM and EN to differentially regulate various signaling pathways and the physiological outcomes. In this communication, we established a system that allowed the specific activations of EGFR at different cell locations: PM and EN. PM activation of EGFR is achieved by activation of endocytosis-deficient mutant EGFR1010LL/AA stably expressed in CHO cells (CHO-LL/AA cell). EN activation of EGFR is achieved by activating the wild type EGFR stably expressed in CHO cells (CHO-EGFR cell) after its internalization into EN with a previously reported protocol. We showed that both EGFR activations at PM and EN activated ERK to a similar level, but differentially stimulated transcriptional factors c-jun and c-fos. We further showed that EGFR activations at PM and EN resulted in differential spatio-temporal dynamics of phosphorylated ERK which caused the differential activation of two downstream substrates ELK1 and RSK. Finally we showed that EGFR signaling from PM and EN led to different physiological outcomes. CHO-LL/AA cells that only generate PM EGFR signals have a larger cell size and slower proliferation rate than CHO-EGFR cells. We conclude that location-specific EGFR activation differentially regulates cell functions through a spatio-temporal interplay of ERK activation.
authors.affiliation: The Department of Medical Genetics and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Wee
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jiang
authors.forename: Xinmei
authors.initials: X
authors.lastname: Chen
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D006224:Cricetinae; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D066246:ErbB Receptors; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate