Presenilin1 (PS1), is a polytopic integral membrane protein that plays important roles in the development of familial Alzheimer's disease (FAD). Classic cadherins are type I transmembrane glycoproteins that control critical events in cell adhesion, recognition, and contact-mediated inhibition of cell growth. Recently we reported that PS1 concentrates at cell-cell and synaptic contact sites where it incorporates into the cadherin/catenin cell-cell adhesion system. Here we present preliminary data that PS1 binds directly to E-cadherin and regulates Ca++-dependent cell-cell adhesion. In addition, our results indicate that PS1 and a gamma-secretase activity control production of a cadherin cytoplasmic peptide of about 20kDa (termed pC20) and regulate expression of both cyclin D1 and cyclin-dependent kinase inhibitor p27Kip1, two important cell cycle proteins. pC20 seems to be derived from a larger cadherin precursor termed pC35. pC35 is produced following an extracytoplasmic cleavage of the full length cadherin. Expression of a cadherin cytoplasmic peptide in PS1-deficient cells mimicked the pC20 effects and reduced the expression levels of both cyclin D1 and p27Kip1. Taken together, our preliminary data suggest that PS1, cadherins, and gamma-secretase are involved in a novel signal transduction mechanism that regulates expression of cell cycle proteins. This mechanism may use the cytoplasmic cadherin-derived peptide pC20 as a messenger which translocates to the nucleus where it controls expression of cell cycle proteins. PS1 and gamma-secretase activity may thus control the cadherin signal transduction pathway by regulating expression of the cadherin-derived message. This application proposes to characterize the cadherin-PS1-gamma-secretase signal transduction pathway and to examine its involvement in Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG008200-18
Application #
6934487
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (02))
Program Officer
Snyder, Stephen D
Project Start
1988-08-01
Project End
2006-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
18
Fiscal Year
2005
Total Cost
$402,563
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Huang, Qian; Voloudakis, Georgios; Ren, Yimin et al. (2018) Presenilin1/?-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15. FASEB J 32:243-253
Warren, Noel A; Voloudakis, Georgios; Yoon, Yonejung et al. (2018) The product of the ?-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis. Cell Mol Life Sci 75:2813-2826
Nikolakopoulou, Angeliki M; Georgakopoulos, Anastasios; Robakis, Nikolaos K (2016) Presenilin 1 promotes trypsin-induced neuroprotection via the PAR2/ERK signaling pathway. Effects of presenilin 1 FAD mutations. Neurobiol Aging 42:41-9
Moreno, José L; Miranda-Azpiazu, Patricia; García-Bea, Aintzane et al. (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5
Zhu, Li; Zhong, Minghao; Elder, Gregory A et al. (2015) Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A 112:11965-70
Bruban, Julien; Voloudakis, Georgios; Huang, Qian et al. (2015) Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotection via ?-secretase-independent transcriptional mechanisms. FASEB J 29:3702-12
Barthet, Gael; Dunys, Julie; Shao, Zhiping et al. (2013) Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiol Aging 34:499-510
Barthet, Gael; Georgakopoulos, Anastasios; Robakis, Nikolaos K (2012) Cellular mechanisms of ýý-secretase substrate selection, processing and toxicity. Prog Neurobiol 98:166-75
Georgakopoulos, Anastasios; Xu, Jindong; Xu, Chijie et al. (2011) Presenilin1/gamma-secretase promotes the EphB2-induced phosphorylation of ephrinB2 by regulating phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk binding protein. FASEB J 25:3594-604
Xu, Jindong; Xilouri, Maria; Bruban, Julien et al. (2011) Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 32:2326.e5-16

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