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J. Biol. Chem., Vol. 282, Issue 12, 9063-9072, March 23, 2007

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Presenilin/-Secretase-mediated Cleavage Regulates Association of Leukocyte-Common Antigen-related (LAR) Receptor Tyrosine Phosphatase with -Catenin^*

Annakaisa Haapasalo, Doo Yeon Kim, Bryce W. Carey, Mari K. Turunen, Warren H. Pettingell, and Dora M. Kovacs¹

From the Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 and the Department of Neuroscience and Neurology, University of Kuopio, 70211 Kuopio, Finland

Leukocyte-common antigen-related (LAR) receptor tyrosine phosphatase regulates cell adhesion and formation of functional synapses and neuronal networks. Here we report that LAR is sequentially cleaved by - and presenilin (PS)/-secretases, which also affect signaling and/or degradation of type-I membrane proteins including the Alzheimer disease-related -amyloid precursor protein. Similar to the previously characterized PS/-secretase substrates, inhibition of -secretase activity resulted in elevated LAR C-terminal fragment (LAR-CTF) levels in stably LAR-overexpressing Chinese hamster ovary (CHO) cells, human neuroglioma cells, and mouse cortical neurons endogenously expressing LAR. Furthermore, LAR-CTF levels increased in cells lacking functional PS, indicating that -secretase-mediated cleavage of LAR was PS-dependent. Inhibition of -secretase activity by TAPI-1 treatment blocked LAR-CTF accumulation, demonstrating that prior ectodomain shedding was prerequisite for PS/-secretase-mediated cleavage of LAR. Moreover, we identified the product of PS/-secretase cleavage, LAR intracellular domain (LICD), both in vitro and in cells overexpressing full-length (FL) LAR or LAR-CTFs. LAR localizes to cadherin--catenin-based cellular junctions. Assembly and disassembly of these junctions are regulated by tyrosine phosphorylation. We found that endogenous tyrosine-phosphorylated -catenin coimmunoprecipitated with LAR in CHO cells. However, when PS/-secretase activity was inhibited, the association between LAR and -catenin significantly diminished. In addition to cell adhesion, -catenin is involved in transcriptional regulation. We observed that LICD significantly decreased transcription of cyclin D1, one of the -catenin target genes. Thus, our results show that PS/-secretase-mediated cleavage of LAR controls LAR--catenin interaction, suggesting an essential role for PS/-secretase in the regulation of LAR signaling.

Received for publication, December 11, 2006

^* This work was supported in part by grants from the National Institutes of Health/NIA (to D. M. K.) and the Academy of Finland (to A. H.). 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 Figs. S1 and S2.

¹ To whom correspondence should be addressed: Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Dept. of Neurology/MIND, Massachusetts General Hospital, Harvard Medical School, 114, 16th St., Charlestown, MA 02129. Tel.: 617-726-3668; Fax: 617-724-1823; E-mail: dora_kovacs{at}hms.harvard.edu.

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