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J. Biol. Chem., Vol. 281, Issue 21, 14547-14553, May 26, 2006

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SorLA Signaling by Regulated Intramembrane Proteolysis^*

Christopher Böhm, Nicole M. Seibel, Birgit Henkel, Harald Steiner, Christian Haass, and Wolfgang Hampe¹

From the University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, D-20246 Hamburg, Germany and the Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany

The single-transmembrane receptor SorLA/LR11 contains binding domains typical for lipoprotein receptors and a VPS10 domain, which binds the neuropeptide head-activator. This undecapeptide enhances proliferation of neuronal precursor cells in a SorLA-dependent manner. Using specific inhibitors we found previously that head activator activates shedding of SorLA by the metalloprotease TACE close to the transmembrane domain releasing the large extra-cellular part of the receptor. Here we show that the remaining COOH-terminal membrane fragment of SorLA is processed by -secretase. Inhibition of -secretase by specific inhibitors or overexpression of dominant negative presenilin mutants and knock out of the presenilin genes led to accumulation of the SorLA membrane fragment and also of full-length SorLA in the membrane. In an in vitro assay we observed the -secretase-dependent release of the two soluble cleavage products, the SorLA cytoplasmic domain and the SorLA -peptide. These processing steps are reminiscent of a novel signaling pathway that has been described for the notch receptor. Here, the notch cytoplasmic domain is released into the cytoplasm by the -secretase and migrates to the nucleus where it acts as a transcriptional regulator. In parallel we found that a fusion protein of the released cytoplasmic tail of SorLA with EGFP located to the nucleus only if the nuclear localization signal of SorLA was intact. In a reporter gene assay the cytoplasmic domain of SorLA acted as a transcriptional activator indicating that SorLA might directly regulate transcription after activation by -secretase.

Received for publication, September 2, 2005 , and in revised form, February 22, 2006.

^* This work was supported by the Deutsche Forschungsgemeinschaft (SFB444B10 and GRK255). 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.

¹ To whom correspondence should be addressed: Inst. für Biochemie und Molekularbiologie 2, Molekulare Zellbiologie, Universitätsklinikum Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Tel.: 49-40-42803-9967; Fax: 49-40-42803-4592; E-mail: hampe{at}uke.uni-hamburg.de.

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