Tumor Necrosis Factor-α Converting Enzyme (TACE) Regulates Epidermal Growth Factor Receptor Ligand Availability

• Published in: The Journal of biological chemistry 2002-04, Vol.277 (15), p.12838
• Main Authors: Susan Wohler Sunnarborg, C. Leann Hinkle, Mary Stevenson, William E. Russell, Christina S. Raska, Jacques J. Peschon, Beverly J. Castner, Mary J. Gerhart, Raymond J. Paxton, Roy A. Black, David C. Lee
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112050200

We previously implicated tumor necrosis factor-α converting enzyme (TACE/ADAM17) in the processing of the integral membrane precursor to soluble transforming growth factor-α (TGF-α), pro-TGF-α. Here we examined TGF-α processing in a physiologically relevant cell model, primary keratinocytes, showing that cells lacking TACE activity shed dramatically less TGF-α as compared with wild-type cultures and that TGF-α cleavage was partially restored by infection of TACE-deficient cells with TACE-encoding adenovirus. Moreover, cotransfection of TACE-deficient fibroblasts with pro-TGF-α and TACE cDNAs increased shedding of mature TGF-α with concomitant conversion of cell-associated pro-TGF-α to a processed form. Purified TACE accurately cleaved pro-TGF-α in vitro at the N-terminal site and also cleaved a soluble form of pro-TGF-α containing only the ectodomain at the C-terminal site. In vitro , TACE accurately cleaved peptides corresponding to cleavage sites of several epidermal growth factor (EGF) family members, and transfection of TACE into TACE-deficient cells increased the shedding of amphiregulin and heparin-binding EGF (HB-EGF) proteins. Consistent with the hypothesis that TACE regulates EGF receptor (EGFR) ligand availability in vivo , mice heterozygous for Tace and homozygous for an impaired EGFR allele ( wa-2 ) were born with open eyes significantly more often than Tace +/+ Egfr wa-2 / wa-2 counterparts. Collectively, these data support a broad role for TACE in the regulated shedding of EGFR ligands.