title: A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions.
abstract: E-cadherin controls a wide array of cellular behaviors including cell-cell adhesion, differentiation and tissue development. Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, controls a gamma-secretase-like cleavage of E-cadherin. This cleavage is stimulated by apoptosis or calcium influx and occurs between human E-cadherin residues Leu731 and Arg732 at the membrane-cytoplasm interface. The PS1/gamma-secretase system cleaves both the full-length E-cadherin and a transmembrane C-terminal fragment, derived from a metalloproteinase cleavage after the E-cadherin ectodomain residue Pro700. The PS1/gamma-secretase cleavage dissociates E-cadherins, beta-catenin and alpha-catenin from the cytoskeleton, thus promoting disassembly of the E-cadherin-catenin adhesion complex. Furthermore, this cleavage releases the cytoplasmic E-cadherin to the cytosol and increases the levels of soluble beta- and alpha-catenins. Thus, the PS1/gamma-secretase system stimulates disassembly of the E-cadherin- catenin complex and increases the cytosolic pool of beta-catenin, a key regulator of the Wnt signaling pathway.
authors.affiliation: Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
authors.forename: Junichi
authors.initials: J
authors.lastname: Shioi
authors.forename: Geo
authors.initials: G
authors.lastname: Serban
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgakopoulos
authors.forename: Shula
authors.initials: S
authors.lastname: Sarner
authors.forename: Vanja
authors.initials: V
authors.lastname: Nagy
authors.forename: Lia
authors.initials: L
authors.lastname: Baki
authors.forename: Paul
authors.initials: P
authors.lastname: Wen
authors.forename: Spiros
authors.initials: S
authors.lastname: Efthimiopoulos
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Shao
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
mesh_terms: D022005:Adherens Junctions; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational
chemical_list: D015820:Cadherins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D020782:Matrix Metalloproteinases