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J. Biol. Chem., Vol. 279, Issue 23, 24179-24188, June 4, 2004

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Selective Roles for Tumor Necrosis Factor -converting Enzyme/ADAM17 in the Shedding of the Epidermal Growth Factor Receptor Ligand Family

THE JUXTAMEMBRANE STALK DETERMINES CLEAVAGE EFFICIENCY^*

C. Leann Hinkle, Susan W. Sunnarborg, David Loiselle, Carol E. Parker, Mary Stevenson¶, William E. Russell¶, and David C. Lee||**

From the Department of Biochemistry and Biophysics, University of North Carolina Proteomics and Mass Spectrometry Facility and ^||Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 and the ^¶Departments of Pediatrics and Cell Biology, Vanderbilt University, Nashville, Tennessee 37232

Epidermal growth factor (EGF) family ligands are derived by proteolytic cleavage of the ectodomains of integral membrane precursors. Previously, we established that tumor necrosis factor -converting enzyme (TACE/ADAM17) is a physiologic transforming growth factor- (TGF-) sheddase, and we also demonstrated enhanced shedding of amphiregulin (AR) and heparin-binding (HB)-EGF upon restoration of TACE activity in TACE-deficient EC-2 fibroblasts. Here we extended these results by showing that purified soluble TACE cleaved single sites in the juxtamembrane stalks of mouse pro-HB-EGF and pro-AR ectodomains in vitro. For pro-HB-EGF, this site matched the C terminus of the purified human growth factor, and we speculate that the AR cleavage site is also physiologically relevant. In contrast, ADAM9 and -10, both implicated in HB-EGF shedding, failed to cleave the ectodomain or cleaved at a nonphysiologic site, respectively. Cotransfection of TACE in EC-2 cells enhanced phorbol myristate acetate-induced but not constitutive shedding of epiregulin and had no effect on betacellulin (BTC) processing. Additionally, soluble TACE did not cleave the juxtamembrane stalks of either pro-BTC or pro-epiregulin ectodomains in vitro. Substitution of the shorter pro-BTC juxtamembrane stalk or truncation of the pro-TGF- stalk to match the pro-BTC length reduced TGF- shedding from transfected cells to background levels, whereas substitution of the pro-BTC P2-P2' sequence reduced TGF- shedding less dramatically. Conversely, substitution of the pro-TGF- stalk or lengthening of the pro-BTC stalk, especially when combined with substitution of the pro-TGF- P2–P2' sequence, markedly increased BTC shedding. These results indicate that efficient TACE cleavage is determined by a combination of stalk length and scissile bond sequence.

Received for publication, November 5, 2003 , and in revised form, March 31, 2004.

^* This work was supported by National Institutes of Health Training Grant CA71341 (to C. L. H.) and Grants CA85410 (to D. C. L.) and DK53804 (to W. E. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, CB 7260, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7260. Tel.: 919-966-5912; Fax: 919-966-2852; E-mail: dclee{at}med.unc.edu.

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