A transforming Src mutant increases the bioavailability of EGFR-ligands via stimulation of the cell surface metalloproteinase ADAM17

Thorsten Maretzky; Wenhui Zhou; Xin-Yun Huang; Carl P Blobel

doi:10.1038/onc.2010.443

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A transforming Src mutant increases the bioavailability of EGFR-ligands via stimulation of the cell surface metalloproteinase ADAM17

Journal article

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A transforming Src mutant increases the bioavailability of EGFR-ligands via stimulation of the cell surface metalloproteinase ADAM17

Thorsten Maretzky, Wenhui Zhou, Xin-Yun Huang and Carl P Blobel

Oncogene, Vol.30(5), pp.611-618

02/03/2011

DOI: 10.1038/onc.2010.443

PMCID: PMC3342068

PMID: 20871631

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https://www.ncbi.nlm.nih.gov/pmc/articles/3342068View

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Abstract

ADAM17 ( a d isintegrin a nd m etalloproteinase 17) 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 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, PAE and HaCaT cells. Src(E378G)-stimulated shedding of TGFα is abolished in Adam17 −/− cells, but can be rescued by wild type 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.

Protein ectodomain shedding

EGF-receptor ligands

ADAM17

Src

EGF-receptor

ERK

Details

Title: Subtitle: A transforming Src mutant increases the bioavailability of EGFR-ligands via stimulation of the cell surface metalloproteinase ADAM17
Creators: Thorsten Maretzky - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, NY, 10021, USA
Wenhui Zhou - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, NY, 10021, USA
Xin-Yun Huang - Department of Physiology, Weill Medical College of Cornell University, New York, NY, 10021, USA
Carl P Blobel - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, NY, 10021, USA
Resource Type: Journal article
Publication Details: Oncogene, Vol.30(5), pp.611-618
DOI: 10.1038/onc.2010.443
PMID: 20871631
PMCID: PMC3342068
NLM abbreviation: Oncogene
ISSN: 0950-9232
eISSN: 1476-5594
Grant note: R01 GM064750-10A1 || GM / National Institute of General Medical Sciences : NIGMS
Language: English
Date published: 02/03/2011
Academic Unit: Internal Medicine
Record Identifier: 9984094526402771

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