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TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase
David C Lee1, Susan Wohler Sunnarborg, C Leann Hinkle
1Department of Biochemistry and Biophysics, UNC-Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7260, USA. dclee@med.unc.edu
Annals of the New York Academy of Sciences
|June 20, 2003
Summary
Tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) is crucial for releasing soluble growth factors like transforming growth factor-alpha (TGFalpha) from their precursor forms. This enzyme
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- EGF family growth factors are released from transmembrane precursors via proteolytic cleavage.
- Identifying the specific proteases responsible for shedding these factors is critical for understanding growth factor regulation.
Purpose of the Study:
- To investigate the role of tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) in the processing of EGF family growth factors.
- To determine if TACE/ADAM17 is responsible for releasing soluble transforming growth factor-alpha (TGFalpha), amphiregulin (AR), and heparin-binding EGF (HB-EGF).
Main Methods:
- Utilized Tace(deltaZn/deltaZn) mice lacking functional TACE/ADAM17 to assess TGFalpha shedding.
- Restored TACE/ADAM17 activity in knockout cells to observe effects on growth factor release.
- Employed exogenous TACE/ADAM17 enzyme for in vitro cleavage assays on proTGFalpha and peptide substrates.
- Examined the impact of TACE/ADAM17 gene dosage on the Egfr(wa-2/wa-2) open-eye defect model.
Main Results:
- Primary keratinocytes from Tace(deltaZn/deltaZn) mice showed significantly reduced soluble TGFalpha levels compared to controls.
- Restoration of TACE/ADAM17 activity in knockout cells rescued TGFalpha shedding.
- Exogenous TACE/ADAM17 demonstrated specific cleavage of proTGFalpha precursor and related peptide substrates.
- TACE/ADAM17 activity enhanced the shedding of soluble AR and HB-EGF, and its deficiency worsened the Egfr(wa-2/wa-2) phenotype.
Conclusions:
- TACE/ADAM17 is a key protease responsible for the shedding of multiple EGF family members, including TGFalpha, AR, and HB-EGF.
- TACE/ADAM17 plays a significant role in the biological functions regulated by EGF family ligands, as evidenced by developmental phenotypes.