Presenilin/gamma-secretase-mediated cleavage regulates association of leukocyte-common antigen-related (LAR) receptor tyrosine phosphatase with beta-catenin.
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 alpha- and presenilin (PS)/gamma-secretases, which also affect signaling and/or degradation of type-I membrane proteins including the Alzheimer disease-related beta-amyloid precursor protein. Similar to the previously characterized PS/gamma-secretase substrates, inhibition of gamma-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 gamma-secretase-mediated cleavage of LAR was PS-dependent. Inhibition of alpha-secretase activity by TAPI-1 treatment blocked LAR-CTF accumulation, demonstrating that prior ectodomain shedding was prerequisite for PS/gamma-secretase-mediated cleavage of LAR. Moreover, we identified the product of PS/gamma-secretase cleavage, LAR intracellular domain (LICD), both in vitro and in cells overexpressing full-length (FL) LAR or LAR-CTFs. LAR localizes to cadherin-beta-catenin-based cellular junctions. Assembly and disassembly of these junctions are regulated by tyrosine phosphorylation. We found that endogenous tyrosine-phosphorylated beta-catenin coimmunoprecipitated with LAR in CHO cells. However, when PS/gamma-secretase activity was inhibited, the association between LAR and beta-catenin significantly diminished. In addition to cell adhesion, beta-catenin is involved in transcriptional regulation. We observed that LICD significantly decreased transcription of cyclin D1, one of the beta-catenin target genes. Thus, our results show that PS/gamma-secretase-mediated cleavage of LAR controls LAR-beta-catenin interaction, suggesting an essential role for PS/gamma-secretase in the regulation of LAR signaling.
Haapasalo
Annakaisa
A
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Kim
Doo Yeon
DY
Carey
Bryce W
BW
Turunen
Mari K
MK
Pettingell
Warren H
WH
Kovacs
Dora M
DM
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D019938:Cyclin D1 / Q000737:chemistry; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D051379:Mice; D053763:Presenilins / Q000378:metabolism / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
D053763:Presenilins; D011956:Receptors, Cell Surface; D051176:beta Catenin; D019938:Cyclin D1; C516841:PTPRA protein, human; D017027:Protein Tyrosine Phosphatases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D053829:Amyloid Precursor Protein Secretases