Structural Features and Biochemical Properties of TNF-Alpha Convertase

Moss, Marcia L.; Jin, Chunyang; Becherer, D J; Bickett, Mark; Burkhart, William; Chen, W.; Clay, William C.; Didsbury, John; Hassler, Daniel F.; Kost, Thomas A.; Leesnitzer, Tony; McGeehan, Gerard M.; McCauley, Philip; Moyer, Mary B.; Milla, Marcos E.; Pahel, Gregory; Rocque, Warren J.; Seaton, Theresa; Warner, Janet; Willard, Derril H.

doi:10.1097/00024382-199703001-00308

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“…The phorbol ester-induced activation of PKC has been shown to induce protein ectodomain shedding of a large variety of cell-surface proteins (Lantz et al 1990, Pandiella & Massague 1991, Mullberg et al 1993, Arribas et al 1996, Black et al 1997, Blobel 1997, Hooper et al 1997, Moss et al 1997. Despite the observation of nonconserved cleavage sites that may be adjacent to the membrane or further out on the molecule, there are clues that a common strategy may operate in membrane protein ectodomain shedding, involving one or several components sensitive to metalloprotease inhibitors (Arribas et al 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact protease(s) responsible for GHR cleavage cannot be ascertained at this time, it may be a member of that family of secretases. The first such secretase characterized was TACE (Black et al 1997, Moss et al 1997, a member of the ADAM subgroup of the metzincin family of proteases which are closely related to the matrix-type metalloprotease family, and the evidence accumulated so far shows that the secretase involved in GHBP shedding shares similar characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of PKC by phorbol esters has frequently been shown to induce ectodomain shedding of a variety of cell-surface proteins (Hooper et al 1997). In addition, metalloproteases have been implicated in the shedding or release of several different cell-surface proteins from the plasma membrane, including various cytokines, cytokine receptors, adhesion proteins and other proteins such as -amyloid precursor protein ( -APP) (Arribas et al 1996, Black et al 1997, Blobel 1997, Hooper et al 1997, Moss et al 1997. In this vein, the recent demonstration that a metalloprotease, presumably tumor necrosis factor (TNF)-converting enzyme (TACE)/a disintegrin and metalloprotease (ADAM)-17, is involved in membrane GHR cleavage (Alele et al 1998, Zhang et al 2000, supports the suggestion that this family of proteases might play a wider role in GHBP generation and secretion from different cells or tissues.…”

Section: Introductionmentioning

confidence: 99%

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Shedding of growth hormone-binding protein is inhibited by hydroxamic acid-based protease inhibitors: proposed mechanism of activation of growth hormone-binding protein secretase

Amit

Hochberg²,

Yogev-Falach³

et al. 2001

Journal of Endocrinology

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The present study describes events postulated to be involved in the regulated mechanism of proteolytic shedding of growth hormone (GH)-binding protein (GHBP). Using Chinese hamster ovary (CHO) cell lines stably transfected either with the full-length human GH receptor (hGHR) or with the cytoplasmic domain-truncated hGHR (hGHR tr ), we show that the phorbol ester, phorbol 12-myristate 13-acetate (PMA), caused a rapid timeand dose-dependent increase in GHBP secretion, which, as expected, was matched by a corresponding decrease in cell-surface GHR. Furthermore, PMA equally enhanced GHBP release from CHO/hGHR tr cells, suggesting that the cytoplasmic domain of hGHR is not essential for PMA-induced shedding. PMA is known to specifically activate protein kinase C and, indeed, the stimulatory effects of PMA in both cell lines were completely inhibited by the protein kinase inhibitor, staurosporine (100 nM), suggesting that activation of protein kinase C (PKC) may mediate PMA-induced GHBP shedding. Since proteolytic cleavage of several cell-surface proteins was shown to be stimulated by modulators of PKC activity and inhibited by metalloprotease inhibitors, we studied the effects of two hydroxamic acid-based inhibitors of zinc-dependent metalloproteases, BB-3103 and Ro31-9790, on GHBP proteolysis. Pretreatment of CHO/hGHR cells with both these inhibitors reduced PMA-enhanced shedding of GHBP, in a dose-dependent manner, with IC 50 values of 0·41 µM for BB-3103 and 0·97 µM for Ro31-9790. In addition, these inhibitors dose-dependently reduced the shedding enhanced by the sulfhydryl alkylator, N-ethylmaleimide (NEM), with IC 50 values of 0·32 µM and 0·58 µM for BB-3103 and Ro31-9790 respectively. It was of interest to find out that Ro31-9790 acted not only to modulate PMA-or NEM-induced shedding processes, but also markedly reduced the spontaneous, time-dependent accumulation of GHBP released from CHO/hGHR cells growing in serum-containing medium. Taken together, these results suggest that one or more zinc-dependent metalloprotease(s), acting at the cell surface, may be involved in GHBP secretase activity. A scheme is proposed whereby at least part of the regulated maturation and/or activation of the protease activity may involve a cysteine-switch mechanism and/or PKCdependent phosphorylation. In the long run, specific inhibitors of these processes could be applied in the regulation of GHBP levels and, thus, of GH availability and/or activity.

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