Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion

Karina Reiss; Thorsten Maretzky; Ingrid G Haas; Marc Schulte; Andreas Ludwig; Marcus Frank; Paul Saftig

doi:10.1074/jbc.M602663200

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Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion

Journal article

Open access

Peer reviewed

Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion

Karina Reiss, Thorsten Maretzky, Ingrid G Haas, Marc Schulte, Andreas Ludwig, Marcus Frank and Paul Saftig

The Journal of biological chemistry, Vol.281(31), pp.21735-21744

08/04/2006

DOI: 10.1074/jbc.M602663200

PMID: 16751190

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Published (Version of record) Open Access

Abstract

Gamma-protocadherins (Pcdh gamma) are type I transmembrane proteins, which are most notably expressed in the nervous system. They are enriched at synapses and involved in synapse formation, specification, and maintenance. In this study, we show that Pcdh gamma C3 and Pcdh gamma B4 are specifically cleaved within their ectodomains by the disintegrin and metalloprotease ADAM10. Analysis of ADAM10-deficient fibroblasts and embryos, inhibitor studies, as well as RNA interference-mediated down-regulation demonstrated that ADAM10 is not only responsible for the constitutive but also for the regulated shedding of these proteins in fibroblasts and in neuronal cells. In contrast to N-cadherin shedding, which was activated by N-methyl-D-aspartic acid receptor activation in neuronal cells, Pcdh gamma shedding was induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate stimulation, suggesting differential regulation mechanisms of cadherin-mediated functions at synapses. Cell aggregation assays in the presence or absence of metalloprotease inhibitors strongly suggest that the ectodomain shedding events modulate the cell adhesion role of Pcdh gamma. The identification of ADAM10 as the protease responsible for constitutive and regulated Pcdh gamma shedding may therefore provide new insight into the regulation of Pcdh gamma functions.

Cell Line

ADAM Proteins - physiology

Cadherins - metabolism

Glutamic Acid - pharmacology

Humans

Cells, Cultured

ADAM10 Protein

Neurons - cytology

Cell Adhesion

Blotting, Western

Mice, Knockout

ADAM Proteins - metabolism

Animals

Membrane Proteins - physiology

Amyloid Precursor Protein Secretases

K562 Cells

Fibroblasts - cytology

Membrane Proteins - metabolism

Mice

Synapses

Details

Title: Subtitle: Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion
Creators: Karina Reiss - Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany
Thorsten Maretzky - Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany
Ingrid G Haas - Max Planck Institute of Immunobiology, Department of Molecular Embryology, Stuebeweg 51, Freiburg D-79108, Germany
Marc Schulte - Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany
Andreas Ludwig - Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany
Marcus Frank - Max Planck Institute of Immunobiology, Department of Molecular Embryology, Stuebeweg 51, Freiburg D-79108, Germany
Paul Saftig - Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany. Electronic address: psaftig@biochem.uni-kiel.de
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.281(31), pp.21735-21744
DOI: 10.1074/jbc.M602663200
PMID: 16751190
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Language: English
Date published: 08/04/2006
Academic Unit: Internal Medicine
Record Identifier: 9984094396002771

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