The Τumor Necrosis Factor-α Converting Enzyme (TACE):  A Unique Metalloproteinase with Highly Defined Substrate Selectivity

Mohan, Mohita J.; Seaton, Theresa; Mitchell, Justin; Howe, Anne; Blackburn, Kevin; Burkhart, William; Moyer, Mary B.; Patel, Indravadan R.; Waitt, Greg; Becherer, J. David; Moss, Marcia L.; Milla, Marcos E.

doi:10.1021/bi0260132

Cited by 186 publications

(82 citation statements)

References 37 publications

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“…When quantitation has been possible, the difference, measured by k cat /K m values, is ϳ10 2 to 10 3 . Also, secondary cleavages in vitro have sometimes been noted (32), similar to what we detected (peptide C) with the ErbB-4 peptide. The underlying reason for the relatively inefficient cleavage in vitro of some peptides by TACE is not understood.…”

Section: Erbb-4 Ectodomain Cleavagesupporting

confidence: 87%

Ectodomain Cleavage of ErbB-4

Cheng

Tikhomirov

Zhou³

et al. 2003

Journal of Biological Chemistry

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Ectodomain cleavage of the ErbB-4 receptor tyrosine kinase generates a membrane-associated fragment of 80 kDa (m80) that has been subjected to N-terminal sequencing. The sequence obtained shows that the N terminus of this fragment begins with Ser-652 of ErbB-4. When a 12-residue peptide corresponding to ErbB-4 residues 646 -657 was incubated with recombinant tumor necrosis factor-␣-converting enzyme, fragments representing residues 646 -651 and 652-657 were obtained. These data indicate that ectodomain cleavage of ErbB-4 occurs between His-651 and Ser-652, placing the cleavage site within the ectodomain stalk region approximately 8 residues prior to the transmembrane domain. Several experiments have characterized other aspects of the m80 ErbB-4 fragment. Inhibition of ErbB-4 tyrosine kinase activity with pan-ErbB tyrosine kinase inhibitors indicates that kinase activity is stringently required for heregulindependent, but not 12-O-tetradecanoylphorbol-13-acetate-induced, ErbB-4 ectodomain cleavage and formation of the m80 fragment. When the m80 ErbB-4 fragment is generated by cell treatment with heregulin or 12-O-tetradecanoylphorbol-13-acetate, the fragment associates with intact ErbB-2. However, this fragment does not associate with the intact ErbB-4 molecule.ErbB-4 is a member of the ErbB receptor tyrosine kinase family, which also includes the epidermal growth factor receptor (ErbB-1), ErbB-2, and ErbB-3 (1). ErbB-4 and ErbB-3 bind the neuregulin (heregulin) family of growth factors, and ErbB-4 also recognizes certain growth factors in the epidermal growth factor family of ErbB-1 agonists, such as betacellulin, epiregulin, and heparin-binding epidermal growth factor. ErbB-4 heterodimerizes with ErbB-2 as do ErbB-1 and ErbB-3; however, ErbB-4 can also signal through the formation of ErbB-4 homodimers.Within the receptor tyrosine kinase family, ErbB-4 is uniquely processed (2) by a proteolytic pathway that is known to occur with certain other transmembrane proteins, such as Notch (3), the low density lipoprotein receptor-related protein (4), the amyloid precursor protein (APP) 1 (5), and the adhesion molecules CD44 (6, 7) and E-cadherin (9). The first step in this pathway involves the release of the ErbB-4 ectodomain by a cleavage that produces two fragments as follows: a 120-kDa ectodomain fragment and an 80-kDa membrane-associated fragment, designated m80 (9). The latter fragment contains the ErbB-4 transmembrane domain and the entire cytoplasmic region, including the tyrosine kinase domain. Ectodomain cleavage of ErbB-4 in cells occurs at a low constitutive or basal level (10) that can be increased by TPA (9) or by heregulin or other growth factors that bind ErbB-4 (11). Also, cleavage is potentiated by the addition to cells of pervanadate, a tyrosine phosphatase inhibitor that provokes ErbB-4 tyrosine phosphorylation (12). The ectodomain cleavage of ErbB-4 is sensitive to metalloprotease inhibitors (10) and does not occur in cells genetically deficient in tumor necrosis factor-␣-converting enzyme (TACE), a ...

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Section: Erbb-4 Ectodomain Cleavagesupporting

confidence: 87%

Ectodomain Cleavage of ErbB-4

Cheng

Tikhomirov

Zhou³

et al. 2003

Journal of Biological Chemistry

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“…The most consistent cleavage site feature among ADAM substrates is that they usually reside in a stalk region between the membrane and an initial globular extracellular subdomain (35). Our findings for the rbGHR cleavage site fit well in this regard with the GHR being an ADAM substrate (34,44). Indeed, the crystal structure suggests that a short stem of roughly ten residues lies between the transmembrane domain and the beginning of extracellular subdomain 2, which contains the receptor dimerization domain (33).…”

supporting

confidence: 80%

Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding

Wang¹,

He²,

Gerhart³

et al. 2002

Journal of Biological Chemistry

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Growth hormone-binding protein (GHBP) is complexed to a substantial fraction of circulating GH. In humans, rabbits, and other species, GHBP derives from proteolytic shedding of the GH receptor (GHR) extracellular domain. In cell culture studies, stimuli such as phorbol ester, platelet-derived growth factor, or serum induce GHR proteolysis, which concomitantly yields shed GHBP in cell supernatants and a cell-associated cytoplasmic domain-containing GHR remnant. This process is sensitive to metalloprotease inhibition, and genetic reconstitution studies identify tumor necrosis factor-␣ converting enzyme (TACE/ADAM-17), a transmembrane metalloprotease, as a GHR sheddase. Stimuli that induce GHR proteolysis render cells less responsive to GH, but the mechanism(s) of this desensitization is not yet understood. In this study, we mapped the rabbit (rb) GHR cleavage site. We adenovirally expressed a C-terminal epitope-tagged rbGHR lacking most of its cytoplasmic domain, purified the remnant protein induced by the phorbol ester, PMA, and derived the cleavage site by N-terminal sequencing of the purified remnant. The N-terminal sequence, 239 FTCEEDFR 246 , matched perfectly the rbGHR and suggests that cleavage occurs eight residues from the membrane in the proximal extracellular domain stem region. Deletion and alanine substitution mutagenesis indicated that, similar to other TACE substrates, the spacing of residues in this region, more than their identity, influences GHR cleavage susceptibility. Further, we determined that PMA pretreatment desensitized a cleavage-sensitive GHR mutant, but not a cleavage-insensitive mutant, to GH-induced JAK2 activation. These results suggest that inducible GHR proteolysis can regulate GH signaling.

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“…Many membrane-anchored proteins are shed from the cell membrane by metalloproteases (51). To identify peptide substrates of ADAM33cat, peptides corresponding to cleavage sites of proteins known to be cleaved by ADAMs and MMPs were tested for cleavage by ADAM33 (7,8,11,41,(51)(52)(53). Table I lists peptides that showed little or no cleavage by ADAM33.…”

Section: Expression and Purification Of Recombinant Humanmentioning

confidence: 99%

“…Table I lists peptides that showed little or no cleavage by ADAM33. Many of these peptides were derived from proteins that are cleaved by other ADAMs such as ADAM17 (TNF-␣-converting enzyme) and ADAM10, (7,52,54), including TNF-␣, TNF receptors I and II, CD40L, interleukin-6 receptor, angiotensinconverting enzyme, Notch, heparin-binding epidermal growth factor, L-selectin, and TGF-␣.…”

Section: Expression and Purification Of Recombinant Humanmentioning

confidence: 99%