ADAM17 (a disintegrin and metalloproteinase 17, also referred to as TNFα 
converting enzyme or TACE) is a cell-surface metalloproteinase that regulates 
signaling via the epidermal growth factor receptor (EGFR) and has important 
roles in diseases such as cancer and rheumatoid arthritis. ADAM17 can be 
activated by stimulation of several tyrosine kinase receptors, raising questions 
about whether oncogenic tyrosine kinases could also enhance EGFR signaling and 
activation of extracellular signal-regulated kinase (ERK) via stimulation of 
ADAM17. The main goal of this study was to evaluate the role of Src in 
activating ADAM17. We provide evidence that a constitutively active transforming 
form of Src, the E378G mutant, as well as v-Src enhance ADAM17-mediated shedding 
of the EGFR ligand TGFα. Moreover, we demonstrate that constitutive shedding of 
TGFα can be reduced by inhibition of Src in several cell lines, including COS7, 
MCF7 (the human breast cancer cell line), PAE (a pig aortic endothelial cell 
line) and HaCaT (the human keratinocyte cell line) cells. Src(E378G)-stimulated 
shedding of TGFα is abolished in Adam17(-/-) cells, but can be rescued by 
wild-type (wt) ADAM17 and a mutant ADAM17 lacking its cytoplasmic domain. These 
findings demonstrate that ADAM17 is the principal TGFα sheddase that is 
activated by Src in a manner that does not require the cytoplasmic domain of 
ADAM17. Finally, we show that stimulation of ADAM17 by Src(E378G) leads to 
enhanced paracrine signaling via release of EGFR ligands into the culture 
supernatant. These results raise the possibility that activation of ADAM17 by 
oncogenic forms of Src can aid in promoting tumorigenesis by enhancing signaling 
via the EGFR and ERK in an autocrine and paracrine manner. Enhanced autocrine 
signaling could further activate tumor cells expressing oncogenic mutants of 
Src, whereas paracrine signaling could stimulate EGFR and ERK signaling in 
surrounding non-transformed cells such as stromal cells, thereby contributing to 
crosstalk between tumor cells and stromal cells.