Presenilin/γ-secretase-mediated cleavage regulates association of Leukocyte-common Antigen-related (LAR) receptor tyrosine phosphatase with β-catenin

Abstract

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 α- and presenilin (PS)/γ-secretases, which also affect signaling and/or degradation of type-I membrane proteins including the Alzheimer disease-related β-amyloid precursor protein. Similar to the previously characterized PS/γ-secretase substrates, inhibition of γ-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 γ-secretase-mediated cleavage of LAR was PS-dependent. Inhibition of γ-secretase activity by TAPI-1 treatment blocked LAR-CTF accumulation, demonstrating that prior ectodomain shedding was prerequisite for PS/γ-secretase-mediated cleavage of LAR. Moreover, we identified the product of PS/γ-secretase cleavage, LAR intracellular domain (LICD), both in vitro and in cells overexpressing full-length (FL) LAR or LAR-CTFs. LAR localizes to cadherin-β-catenin-based cellular junctions. Assembly and disassembly of these junctions are regulated by tyrosine phosphorylation. We found that endogenous tyrosine-phosphorylated β-catenin coimmunoprecipitated with LAR in CHO cells. However, when PS/γ-secretase activity was inhibited, the association between LAR and β-catenin significantly diminished. In addition to cell adhesion, β-catenin is involved in transcriptional regulation. We observed that LICD significantly decreased transcription of cyclin D1, one of the β-catenin target genes. Thus, our results show that PS/γ-secretase-mediated cleavage of LAR controls LAR-β-catenin interaction, suggesting an essential role for PS/γ-secretase in the regulation of LAR signaling. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.