scholarly journals The Tetraspanin Cd9 Associates with Transmembrane TGF-α and Regulates TGF-α–Induced Egf Receptor Activation and Cell Proliferation

2000 ◽  
Vol 148 (3) ◽  
pp. 591-602 ◽  
Author(s):  
Wen Shi ◽  
Huizhou Fan ◽  
Lillian Shum ◽  
Rik Derynck
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Receptor Activation ◽  
Tyrosine Kinase Receptor ◽  
Transforming Growth Factor Α ◽  
Egfr Activation ◽  
Membrane Spanning ◽  
Factor Α

Transforming growth factor-α (TGF-α) is a member of the EGF growth factor family. Both transmembrane TGF-α and the proteolytically released soluble TGF-α can bind to the EGF/TGF-α tyrosine kinase receptor (EGFR) and activate the EGFR-induced signaling pathways. We now demonstrate that transmembrane TGF-α physically interacts with CD9, a protein with four membrane spanning domains that is frequently coexpressed with TGF-α in carcinomas. This interaction was mediated through the extracellular domain of transmembrane TGF-α. CD9 expression strongly decreased the growth factor– and PMA- induced proteolytic conversions of transmembrane to soluble TGF-α and strongly enhanced the TGF- α–induced EGFR activation, presumably in conjunction with increased expression of transmembrane TGF-α. In juxtacrine assays, the CD9-induced EGFR hyperactivation by transmembrane TGF-α resulted in increased proliferation. In contrast, CD9 coexpression with transmembrane TGF-α decreased the autocrine growth stimulatory effect of TGF-α in epithelial cells. This decrease was associated with increased expression of the cdk inhibitor, p21CIP1. These data reveal that the association of CD9 with transmembrane TGF-α regulates ligand-induced activation of the EGFR, and results in altered cell proliferation.

scholarly journals EGF and amphiregulin differentially regulate Cbl recruitment to endosomes and EGF receptor fate

2008 ◽  
Vol 410 (3) ◽  
pp. 585-594 ◽  
Author(s):  
Kathryn A. Stern ◽  
Trenton L. Place ◽  
Nancy L. Lill
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Partial Agonist ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Transforming Growth Factor Α ◽  
Molecular Events ◽  
Factor Α

EGF-R [EGF (epidermal growth factor) receptor] ligands can promote or inhibit cell growth. The biological outcome of receptor activation is dictated, at least in part, by ligand-specified patterns of endocytic trafficking. EGF-R trafficking downstream of the ligands EGF and TGF-α (transforming growth factor-α) has been investigated extensively. However, less is known about EGF-R fates induced by the ligands BTC (betacellulin) and AR (amphiregulin). We undertook comparative analyses to identify ligand-specific molecular events that regulate EGF-R trafficking and degradation. EGF (17 nM) and BTC (8.5 nM) induced significant EGF-R degradation, with or without ectopic expression of the ubiquitin ligase Cbl. Human recombinant AR (17 nM) failed to affect receptor degradation in either case. Notably, levels of ligand-induced EGF-R ubiquitination did not correlate strictly with receptor degradation. Dose–response experiments revealed that AR at a saturating concentration was a partial agonist at the EGF-R, with approx. 40% efficacy (relative to EGF) at inducing receptor tyrosine phosphorylation, ubiquitination and association with Cbl. EGF-R down-regulation and degradation also were compromised upon cell stimulation with AR (136 nM). These outcomes correlated with decreased degradation of the Cbl substrate and internalization inhibitor hSprouty2. Downstream of the hSprouty2 checkpoint in AR-stimulated cells, Cbl-free EGF-R was incorporated into endosomes from which Cbl–EGF-R complexes were excluded. Our results suggest that the AR-specific EGF-R fate results from decreased hSprouty2 degradation and reduced Cbl recruitment to underphosphorylated EGF-R, two effects that impair EGF-R trafficking to lysosomes.

EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-α-induced pulmonary fibrosis

2008 ◽  
Vol 294 (6) ◽  
pp. L1217-L1225 ◽  
Author(s):  
William D. Hardie ◽  
Cynthia Davidson ◽  
Machiko Ikegami ◽  
George D. Leikauf ◽  
Timothy D. Le Cras ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Pulmonary Mechanics ◽  
Transforming Growth Factor Α ◽  
Egfr Activation ◽  
Factor Α

Transforming growth factor-α (TGF-α) is a ligand for the EGF receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. We determined the effects of EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) on the development and progression of TGF-α-induced pulmonary fibrosis. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-α expression, we determined effects of treatment with gefitinib and erlotinib on changes in lung histology, total lung collagen, pulmonary mechanics, pulmonary hypertension, and expression of genes associated with synthesis of ECM and vascular remodeling. Induction in the lung of TGF-α caused progressive pulmonary fibrosis over an 8-wk period. Daily administration of gefitinib or erlotinib prevented development of fibrosis, reduced accumulation of total lung collagen, prevented weight loss, and prevented changes in pulmonary mechanics. Treatment of mice with gefitinib 4 wk after the induction of TGF-α prevented further increases in and partially reversed total collagen levels and changes in pulmonary mechanics and pulmonary hypertension. Increases in expression of genes associated with synthesis of ECM as well as decreases of genes associated with vascular remodeling were also prevented or partially reversed. Administration of gefitinib or erlotinib did not cause interstitial fibrosis or increases in lavage cell counts. Administration of small molecule EGFR tyrosine kinase inhibitors prevented further increases in and partially reversed pulmonary fibrosis induced directly by EGFR activation without inducing inflammatory cell influx or additional lung injury.

scholarly journals Mitochondrial Reactive Oxygen Species Mediate GPCR–induced TACE/ADAM17-dependent Transforming Growth Factor-α Shedding

2009 ◽  
Vol 20 (24) ◽  
pp. 5236-5249 ◽  
Author(s):  
Timothy J. Myers ◽  
Leann H. Brennaman ◽  
Mary Stevenson ◽  
Shigeki Higashiyama ◽  
William E. Russell ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Ros Scavenging ◽  
Transforming Growth Factor Α ◽  
Egfr Activation ◽  
Mitochondrial Ros ◽  
Factor Α

Epidermal growth factor receptor (EGFR) activation by GPCRs regulates many important biological processes. ADAM metalloprotease activity has been implicated as a key step in transactivation, yet the regulatory mechanisms are not fully understood. Here, we investigate the regulation of transforming growth factor-α (TGF-α) shedding by reactive oxygen species (ROS) through the ATP-dependent activation of the P2Y family of GPCRs. We report that ATP stimulates TGF-α proteolysis with concomitant EGFR activation and that this process requires TACE/ADAM17 activity in both murine fibroblasts and CHO cells. ATP-induced TGF-α shedding required calcium and was independent of Src family kinases and PKC and MAPK signaling. Moreover, ATP-induced TGF-α shedding was completely inhibited by scavengers of ROS, whereas calcium-stimulated shedding was partially inhibited by ROS scavenging. Hydrogen peroxide restored TGF-α shedding after calcium chelation. Importantly, we also found that ATP-induced shedding was independent of the cytoplasmic NADPH oxidase complex. Instead, mitochondrial ROS production increased in response to ATP and mitochondrial oxidative complex activity was required to activate TACE-dependent shedding. These results reveal an essential role for mitochondrial ROS in regulating GPCR-induced growth factor shedding.

scholarly journals Interactive Effects of c-myc and Transforming Growth Factor α Transgenes on Liver Tumor Development in Simian Virus 40 T Antigen Transgenic Mice

1998 ◽  
Vol 35 (4) ◽  
pp. 283-291 ◽  
Author(s):  
A. Enomoto ◽  
E. P. Sandgren ◽  
R. R. Maronpot
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Liver Tumors ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Transforming Growth Factor Α ◽  
Neoplastic Lesions ◽  
Factor Α

To analyze the effects of c- myc and transforming growth factor α (TGFα) on hepatocarcinogenesis induced by simian virus 40 T antigen (TAg), livers from single and bitransgenic mice, 3 to 11 mice per line, were examined morphologically 1 to 8 weeks after birth. Mice carrying c- myc or TGFα alone exhibited centrilobular hypertrophy and increased apoptosis (c- myc mice only) of hepatocytes after 3 or 4 weeks of age, but no detectable changes in cell proliferation or proliferative lesions were observed in either line during the 8 weeks. Mice carrying TAg alone exhibited increased cell proliferation, apoptosis, and dysplasia of hepatocytes with notably high mitotic and apoptotic indices as major changes before development of putative preneoplastic lesions after 4 weeks of age and neoplastic lesions after 6 weeks. In bitransgenic mice coexpressing c- myc or TGFα with TAg, nonproliferative lesions and mitotic and apoptotic indices were similar to those in mice carrying TAg alone. In TAg X c- myc bitransgenic mice, however, both preneoplastic and neoplastic lesions developed sooner and grew more rapidly than those in TAg mice, whereas in TAg X TGFα bitransgenic mice, rapid tumor growth was the principle observation. Because of the effects of transgene coexpression, livers from TAg X c- myc and TAg X TGFα mice had multiple tumors as early as 3 and 6 weeks of age, respectively. The results indicate cooperative functions of c- myc and TGFα with TAg during development and/or growth of liver tumors in vivo.

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