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1.  TNF-α–Converting Enzyme/A Disintegrin and Metalloprotease−17 Mediates Mechanotransduction in Murine Tracheal Epithelial Cells 
Bronchoconstriction applies compressive stress to airway epithelial cells. We show that the application of compressive stress to cultured murine tracheal epithelial cells elicits the increased phosphorylation of extracellular signal–regulated kinase (ERK) and Akt through an epidermal growth factor receptor (EGFR)–dependent process, consistent with previous observations of the bronchoconstriction-induced activation of EGFR in both human and murine airways. Mechanotransduction requires metalloprotease activity, indicating a pivotal role for proteolytic EGF-family ligand shedding. However, cells derived from mice with targeted deletions of the EGFR ligands Tgfα and Hb-egf showed only modest decreases in responses, even when combined with neutralizing antibodies to the EGFR ligands epiregulin and amphiregulin, suggesting redundant or compensatory roles for individual EGF family members in mechanotransduction. In contrast, cells harvested from mice with a conditional deletion of the gene encoding the TNF-α–converting enzyme (TACE/ADAM17), a sheddase for multiple EGF-family proligands, displayed a near-complete attenuation of ERK and Akt phosphorylation responses and compressive stress–induced gene regulation. Our data provide strong evidence that TACE plays a critical central role in the transduction of compressive stress.
PMCID: PMC3175563  PMID: 21097655
asthma; airway remodelling; TACE
2.  The Epidermal Growth Factor Receptor Promotes Glomerular Injury and Renal Failure in Rapidly Progressive Crescentic Glomerulonephritis; the Identification of Possible Therapy 
Nature Medicine  2011;17(10):1242-1250.
Rapidly progressive glomerulonephritis (RPGN) is a clinical a morphological expression of severe glomerular injury. Glomerular injury manifests as a proliferative histological pattern (“crescents”) with accumulation of T cells and macrophages, and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the EGFR/ErbB1 receptor in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 days after the induction of experimental RPGN. This suggests that targeting the HB-EGF/EGFR pathway could also be beneficial for treatment of human RPGN.
PMCID: PMC3198052  PMID: 21946538
3.  Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin 
Development (Cambridge, England)  2005;132(17):3923-3933.
Epithelial-mesenchymal crosstalk is essential for tissue morphogenesis, but incompletely understood. Postnatal mammary gland development requires epidermal growth factor receptor (EGFR) and its ligand amphiregulin (AREG), which generally must be cleaved from its transmembrane form in order to function. As the transmembrane metalloproteinase ADAM17 can process AREG in culture and Adam17−/− mice tend to phenocopy Egfr−/− mice, we examined the role of each of these molecules in mammary development. Tissue recombination and transplantation studies revealed that EGFR phosphorylation and ductal development occur only when ADAM17 and AREG are expressed on mammary epithelial cells, whereas EGFR is required stromally, and that local AREG administration can rescue Adam17−/− transplants. Several EGFR agonists also stimulated Adam17−/− mammary organoid growth in culture, but only AREG was expressed abundantly in the developing ductal system in vivo. Thus, ADAM17 plays a crucial role in mammary morphogenesis by releasing AREG from mammary epithelial cells, thereby eliciting paracrine activation of stromal EGFR and reciprocal responses that regulate mammary epithelial development.
PMCID: PMC2771180  PMID: 16079154
Mammary gland; Branching morphogenesis; Metalloproteinase; ADAMs; TNFα converting enzyme; ERBB; Stromal-epithelial interactions; Epidermal growth factor receptor; Mouse
4.  Heparin-binding EGF-like Growth Factor Signaling in Flow-induced Arterial Remodeling 
Circulation research  2008;102(10):1275-1285.
Heparin-binding EGF-like growth factor (HB-EGF) is activated by reduced endothelial shear stress and stimulates smooth muscle cell (SMC) proliferation in vitro. More- over, HB-EGF is augmented at sites of intimal hyperplasia and atherosclerosis— conditions favored by low/disturbed shear stress. We thus tested whether HB-EGF contributes to low Flow-Induced NUegative hypertrophic Remodeling (FINR) of mouse carotid artery. Blood flow was surgically decreased in the left and increased in the right common carotids. After 21 days, left carotid exhibited lumen narrowing, thickening of intima-media and adventitia, and increased circumference that were inhibited by ~50% in HB-EGF+/- and ~90% in HB-EGF-/- mice. FINR was also inhibited by the EGF receptor inhibitor, AG1478. In contrast, eutrophic outward remodeling of the right carotid was unaffected in HB-EGF+/- and HB-EGF-/- mice or by AG1478. FINR-induced proliferation and leukocyte accumulation were reduced in HB-EGF-/-. FINR was associated with increased: reactive oxygen species, expression of pro-HB-EGF and TACE (pro-HB-EGF sheddase), phosphorylation of EGFR and Erk1/2, and NF-κB activity. Apocynin and deletion of p47phox inhibited FINR, while deletion of HB-EGF abolished NF-κB activation in SMCs. These findings suggest that HB-EGF signaling is required for low flow-induced hypertrophic remodeling and may participate in vascular wall disease and remodeling.
PMCID: PMC2752633  PMID: 18436796
artery; flow-mediated remodeling; HB-EGF; reactive oxygen species; NF-ķB
5.  The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer 
In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra- and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17–AREG–EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.
PMCID: PMC2723838  PMID: 18470483
Mammary gland; Branching morphogenesis; Metalloproteinase; ADAMs; TNFα converting enzyme; ErbB; Stromal-epithelial interactions; Epidermal growth factor receptor
6.  Timp3 deficiency in insulin receptor–haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-α 
Journal of Clinical Investigation  2005;115(12):3494-3505.
Activation of inflammatory pathways may contribute to the beginning and the progression of both atherosclerosis and type 2 diabetes. Here we report a novel interaction between insulin action and control of inflammation, resulting in glucose intolerance and vascular inflammation and amenable to therapeutic modulation. In insulin receptor heterozygous (Insr+/–) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-α–converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. Among Insr+/– mice, those that develop diabetes have reduced Timp3 and increased TACE activity. Unchecked TACE activity causes an increase in levels of soluble TNF-α, which subsequently promotes diabetes and vascular inflammation. Double heterozygous Insr+/–Timp3+/– mice develop mild hyperglycemia and hyperinsulinemia at 3 months and overt glucose intolerance and hyperinsulinemia at 6 months. A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/– diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/– mice compared with WT mice. Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation.
PMCID: PMC1283942  PMID: 16294222

Results 1-6 (6)