Journal of Biological Chemistry
Volume 280, Issue 49, 9 December 2005, Pages 40624-40631
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Molecular Basis of Cell and Developmental Biology
The Disintegrin ADAM9 Indirectly Contributes to the Physiological Processing of Cellular Prion by Modulating ADAM10 Activity*

https://doi.org/10.1074/jbc.M506069200Get rights and content
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The cellular prion protein (PrPc) is physiologically cleaved in the middle of its 106–126 amino acid neurotoxic region at the 110/111↓112 peptidyl bond, yielding an N-terminal fragment referred to as N1. We recently demonstrated that two disintegrins, namely ADAM10 and ADAM17 (TACE, tumor necrosis factor alpha converting enzyme) participated in both constitutive and protein kinase C-regulated generation of N1, respectively. These proteolytic events were strikingly reminiscent of those involved in the so-called “α-secretase pathway” that leads to the production of secreted sAPPα from βAPP. We show here, by transient and stable transfection analyses, that ADAM9 also participates in the constitutive secretion of N1 in HEK293 cells, TSM1 neurons, and mouse fibroblasts. Decreasing endogenous ADAM9 expression by an antisense approach drastically reduces both N1 and sAPPα recoveries. However, we establish that ADAM9 was unable to increase N1 and sAPPα productions after transient transfection in fibroblasts depleted of ADAM10. Accordingly, ADAM9 is unable to cleave a fluorimetric substrate of membrane-bound α-secretase activity in ADAM10-/- fibroblasts. However, we establish that co-expression of ADAM9 and ADAM10 in ADAM10-deficient fibroblasts leads to enhanced membrane-bound and released fluorimetric substrate hydrolyzing activity when compared with that observed after ADAM10 cDNA transfection alone in ADAM10-/- cells. Interestingly, we demonstrate that shedded ADAM10 displays the ability to cleave endogenous PrPc in fibroblasts. Altogether, these data provide evidence that ADAM9 is an important regulator of the physiological processing of PrPc and βAPP but that this enzyme acts indirectly, likely by contributing to the shedding of ADAM10. ADAM9 could therefore represent, besides ADAM10, another potential therapeutic target to enhance the breakdown of the 106–126 and Aβ toxic domains of the prion and βAPP proteins.

Cited by (0)

1

Supported by the “Groupement d'Intérêt Scientifique: Infections à Prions 2001.”

2

Supported by Aventis Pharma.

*

This work was supported by the Centre National de la Recherche Scientifique and by European Union Contract LSHM-CT-2003-503330 (APOPIS). 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.