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J. Biol. Chem., Vol. 278, Issue 44, 42829-42839, October 31, 2003

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Phorbol 12-Myristate 13-Acetate-induced Ectodomain Shedding and Phosphorylation of the Human Meprin Metalloprotease^*

Dagmar Hahn, Anastassios Pischitzis, Sandra Roesmann, Marianne K. Hansen¶, Boris Leuenberger, Ursula Luginbuehl, and Erwin E. Sterchi||

From the Institute of Biochemistry and Molecular Biology and Department of Pediatrics, Berne University, 3012 Berne, Switzerland

Shedding of proteins localized at the cell surface is an important regulatory step in the function of many of these proteins. Human meprin (N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase, PPH, EC 3.4.24.18) a zinc-metalloendopeptidase of the astacin family is an oligomeric protein complex of - and -subunits and is expressed abundantly in the intestine and kidney as well as in leukocytes of the lamina propria and in cancer cells. In transfected cells intracellular proteolytic removal of the membrane anchor results in the secretion of the meprin -subunit. In rats and mice, the -subunit exists in a membrane-anchored form. In contrast, human meprin is constitutively converted into a secretable form. We now show that phorbol 12-myristate 13-acetate (PMA) stimulates an increased release of hmeprin from transfected COS-1 cells, whereas hmeprin secretion is not influenced. This stimulatory effect is inhibited by the protein kinase C (PKC) inhibitor staurosporine, suggesting that activation of PKC mediates PMA-induced hmeprin shedding. The use of different protease inhibitors shows that two different metalloprotease activities are responsible for the constitutive and the PMA-stimulated hmeprin shedding. We identified tumor necrosis factor -converting enzyme (TACE or ADAM17) as the protease that mediates the PMA-induced release. We also demonstrate that hmeprin is phosphorylated by PMA treatment on Ser⁶⁸⁷ within a PKC consensus sequence in the cytosolic domain of the protein. This phosphorylation of hmeprin is not, however, implicated in the enhanced secretion by PMA treatment.

Received for publication, October 31, 2002 , and in revised form, August 11, 2003.

^* This work was supported by Swiss National Science Foundation Grant 3200-052736.97 (to E. S.). 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.

Present address: Chemical Central Laboratories, Inselspital, 3010 Berne, Switzerland.

Present address: Kronenpat, 70035 Stuttgart, Germany.

^¶ Present address: Symphogen A/S, 2800 Lyngby, Denmark.

^|| To whom correspondence should be addressed: Institute of Biochemistry and Molecular Biology, Bühlstrasse 28, 3012 Berne, Switzerland. Tel.: 41-31-631-41-99; Fax: 41-31-631-37-37; E-mail: erwin.sterchi{at}mci.unibe.ch.

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