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J. Biol. Chem., Vol. 280, Issue 10, 9313-9319, March 11, 2005

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Presenilin-dependent Processing and Nuclear Function of -Protocadherins^*

Ingrid G. Haas, Marcus Frank, Nathalie Véron, and Rolf Kemler

From the Max-Planck Institute of Immunobiology, Department of Molecular Embryology, Stuebeweg 51, Freiburg D-79108, Germany

The recently described protocadherin gene clusters encode cadherin-related proteins, which are highly expressed in the vertebrate nervous system. Here, we report biochemical studies addressing proteolytic processing of -protocadherins. These type-I transmembrane proteins are cleaved by a metalloproteinase in vivo, generating a soluble extracellular fragment and a carboxyl-terminal fragment associated with the cellular membrane. In addition, we show that the carboxyl-terminal fragment is a substrate for further cleavage mediated by presenilin. Consequently, accumulation of the fragment is found when -secretase is inactivated either by the specific presenilin-inhibitor L685,458 or in double mutant murine embryonic fibroblasts lacking both presenilin genes. The -secretase-generated carboxyl-terminal fragment is largely unstable but accumulates when proteasomal degradation is inhibited. Interestingly, the proteolytic fragment generated by -secretase can localize to the nucleus. This is the first report providing experimental evidence for a cell surface receptor signaling function of protocadherins regulated by proteolytic events.

Received for publication, November 15, 2004

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB592/B5 (to R. K.). 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: Max-Planck Institute of Molecular Genetics, Department of Developmental Genetics, Ihnestr. 63–73, Berlin D-14195, Germany.

To whom correspondence should be addressed. Tel.: 49-761-5108-475; Fax: 49-761-5108-474; E-mail: haasi{at}immunbio.mpg.de.

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