c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling Journal Article

Authors: Donepudi, M.; Resh, M. D.
Article Title: c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling
Abstract: c-Src is a non-receptor tyrosine kinase that associates with both the plasma membrane and endosomal compartments. In many human cancers, especially breast cancer, c-Src and the EGF receptor (EGFR) are overexpressed. Dual overexpression of c-Src and EGFR correlates with a Src-dependent increase in activation of EGFR, and synergism between these two tyrosine kinases increases the mitogenic activity of EGFR. Despite extensive studies of the functional interaction between c-Src and EGFR, little is known about the interactions in the trafficking pathways for the two proteins and how that influences signaling. Given the synergism between c-Src and EGFR, and the finding that EGFR is internalized and can signal from endosomes, we hypothesized that c-Src and EGFR traffic together through the endocytic pathway. Here we use a regulatable c-SrcGFP fusion protein that is a bona fide marker for c-Src to show that c-Src undergoes constitutive macropinocytosis from the plasma membrane into endocytic compartments. The movement of c-Src was dependent on its tyrosine kinase activity. Stimulation of cells with EGF revealed that c-Src traffics into the cell with activated EGFR and that c-Src expression and kinase activity prolongs EGFR activation. Surprisingly, even in the absence of EGF addition, c-Src expression induced activation of EGFR and of EGFR-mediated downstream signaling targets ERK and Shc. These data suggest that the synergy between c-Src and EGFR also occurs as these two kinases traffic together, and that their co-localization promotes EGFR-mediated signaling. © 2008 Elsevier Inc. All rights reserved.
Keywords: signal transduction; epidermal growth factor; controlled study; protein expression; human cell; protein localization; animals; mice; cell compartmentalization; epidermal growth factor receptor; receptor, epidermal growth factor; enzyme activation; enzyme activity; protein tyrosine kinase; cercopithecus aethiops; cos cells; hybrid protein; recombinant fusion proteins; cell membrane; protein transport; ligands; green fluorescent proteins; genes, reporter; cell stimulation; tyrosine kinase; endocytosis; subcellular fractions; nih 3t3 cells; chickens; endosome; intracellular space; proto-oncogene proteins pp60(c-src); c-src; vesicular transport proteins; endosomes; egf receptor; macropinocytosis; oncogene src; pinocytosis
Journal Title: Cellular Signalling
Volume: 20
Issue: 7
ISSN: 0898-6568
Publisher: Elsevier Inc.  
Date Published: 2008-07-01
Start Page: 1359
End Page: 1367
Language: English
DOI: 10.1016/j.cellsig.2008.03.007
PUBMED: 18448311
PROVIDER: scopus
PMCID: PMC2459337
Notes: --- - "Cited By (since 1996): 24" - "Export Date: 17 November 2011" - "CODEN: CESIE" - "Source: Scopus"
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  1. Marilyn D Resh
    101 Resh