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J. Biol. Chem., Vol. 283, Issue 18, 12004-12013, May 2, 2008

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The Functional Role of the Second NPXY Motif of the LRP1 β-Chain in Tissue-type Plasminogen Activator-mediated Activation of N-Methyl-D-aspartate Receptors^*

Anne M. Martin, Christoph Kuhlmann, Svenja Trossbach, Sebastian Jaeger, Elaine Waldron, Anton Roebroek^¶, Heiko J. Luhmann, Alexander Laatsch^||, Sascha Weggen^**, Volkmar Lessmann, and Claus U. Pietrzik¹

From the Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration and Institute of Physiology, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany, ^¶Experimental Mouse Genetics, Department of Human Genetics, KU Leuven and Flanders Institute for Biotechnology, B-3000 Leuven, Belgium, the ^||Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany, ^**Institute of Neuropathology, Department of Molecular Neuropathology, University Medical Center Heinrich-Heine-University, D-40225 Düsseldorf, Germany and Institute of Physiology, Otto-von-Guericke-University, D-39120 Magdeburg, Germany

The low density lipoprotein receptor-related protein 1 (LRP1) emerges to play fundamental roles in cellular signaling pathways in the brain. One of its prominent ligands is the serine proteinase tissue-type plasminogen activator (tPA), which has been shown to act as a key activator of neuronal mitogen-activated protein kinase pathways via the N-methyl-D-aspartate (NMDA) receptor. However, here we set out to examine whether LRP1 and the NMDA receptor might eventually act in a combined fashion to mediate tPA downstream signaling. By blocking tPA from binding to LRP1 using the receptor-associated protein, we were able to completely inhibit NMDA receptor activation. Additionally, inhibition of NMDA receptor calcium influx with MK-801 resulted in dramatic reduction of tPA-mediated downstream signaling. This indicates a functional interaction between the two receptors, since both experimental approaches resulted in strongly reduced calcium influx and Erk1/2 phosphorylation. Additionally, we were able to inhibit Erk1/2 activation by competing for the LRP1 C-terminal binding motif with a truncated PSD95 construct resembling its PDZ III domain. Furthermore, we identified the distal NPXY amino acid motif in the C terminus of LRP1 as the crucial element for LRP1-NMDA receptor interaction via the adaptor protein PSD95. These results provide new insights into the mechanism of a tPA-induced, LRP1-mediated gating mechanism for NMDA receptors.

Received for publication, September 11, 2007 , and in revised form, February 11, 2008.

^* This work was supported by Deutsche Forschungsgemeinschaft (DFG) Grant PI379 3-3 (to C. U. P.), Stiftung Rheinland-Pfalz (to C. U. P.), and DFG Sonderforschungsbereich (to V. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany. Tel.: 49-6131-3925390; Fax: 49-6131-3926844; E-mail: pietrzik{at}uni-mainz.de.

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