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J. Biol. Chem., Vol. 278, Issue 49, 48651-48657, December 5, 2003

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Syndecan 3 Intramembrane Proteolysis Is Presenilin/-Secretase-dependent and Modulates Cytosolic Signaling^*

Joachim G. Schulz¶||, Wim Annaert¶**, Joël Vandekerckhove¶, Pascale Zimmermann¶**, Bart De Strooper¶, and Guido David¶¶¶

From the Glycobiology and Developmental Genetics and the Neuronal Cell Biology Group, Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium, Department of Medical Protein Research, University of Gent, 9000 Gent, Belgium, and ^¶ Flanders Interuniversity Institute for Biotechnology, 9052 Gent, Belgium

The syndecans play critical roles in several signal transduction pathways. The core proteins of these heparan sulfate proteoglycans are characterized by highly conserved transmembrane and intracellular domains which are required for signaling across the membrane and for interaction with cytosolic proteins. However, regulatory mechanisms controlling these functions remain largely unknown. Here we show that, upon ligand-induced primary proteolytic cleavage within the ectodomain, the intracellular domain of syndecan 3 is released by regulated intramembrane proteolysis. The cleavage is mediated by presenilin/-secretase complex and negatively regulates the plasma membrane targeting of the transcriptional cofactor CASK.

Received for publication, July 31, 2003 , and in revised form, September 17, 2003.

This paper is dedicated to the memory of Dr. Merton R. Bernfield.

^* This work was supported by grants from the Flanders Interuniversity Institute for Biotechnology, the FWO-Flanders, the European Union (Diadem), the Belgian Government (Interuniversity Attraction Pole program), Concerted Actions Program Grant GOA 2001/06 (to G. D.), and an Alzheimer's Association Pioneer Award (to B. D. 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.

^|| Supported by a Deutsche Forschungsgemeinschaft postdoctoral fellowship.

^** Postdoctoral investigators of the FWO-Flanders.

To whom correspondence should be addressed. Tel.: 32-16-346227; Fax: 32-16-347181; E-mail: ad{at}med.kuleuven.ac.be. ¶¶ To whom correspondence should be addressed: Dept. of Human Genetics, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32-16-347167; Fax: 32-16-347166; E-mail: guido.david{at}med.kuleuven.ac.be.

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