Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor.

Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. Research Abstract Details 

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Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. Abstract Text:

Claudia Litterst,Anastasios Georgakopoulos,Junichi Shioi,Enrico Ghersi,Thomas Wisniewski,Rong Wang,Andreas Ludwig,Nikolaos K Robakis,

Binding of EphB receptors to ephrinB ligands on the surface of adjacent cells initiates signaling cascades that regulate angiogenesis, axonal guidance, and neuronal plasticity. These functions require processing of EphB receptors and removal of EphB-ephrinB complexes from the cell surface, but the mechanisms involved are poorly understood. Here we show that the ectodomain of EphB2 receptor is released to extracellular space following cleavage after EphB2 residue 543. The remaining membrane-associated fragment is cleaved by the presenilin-dependent gamma-secretase activity after EphB2 residue 569 releasing an intracellular peptide that contains the cytoplasmic domain of EphB2. This cleavage is inhibited by presenilin 1 familial Alzheimer disease mutations. Processing of EphB2 receptor depends on specific treatments: ephrinB ligand-induced processing requires endocytosis, and the ectodomain cleavage is sensitive to peptide inhibitor N-benzyloxycarbonyl-Val-Leu-leucinal but insensitive to metalloproteinase inhibitor GM6001. The ligand-induced processing takes place in endosomes and involves the rapid degradation of the extracellular EphB2. EphrinB ligand stimulates ubiquitination of EphB2 receptor. Calcium influx- and N-methyl-d-aspartic acid-induced processing of EphB2 is inhibited by GM6001 and ADAM10 inhibitors but not by N-benzyloxycarbonyl-Val-Leu-leucinal. This processing requires no endocytosis and promotes rapid shedding of extracellular EphB2, indicating that it takes place at the plasma membrane. Our data identify novel cleavages and modifications of EphB2 receptor and indicate that specific conditions determine the proteolytic systems and subcellular sites involved in the processing of this receptor.

Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. Publishing Authors By Initials

C Litterst,A Georgakopoulos,J Shioi,E Ghersi,T Wisniewski,R Wang,A Ludwig,NK Robakis,

For similar enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: receptor protein-tyrosine kinases: receptors, eph family: receptor, ephb2 research abstracts see: enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: receptor protein-tyrosine kinases: receptors, eph family: receptor, ephb2 research

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Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 16155-63

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 10

MONTH: 04

YEAR: 2007

Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. Keywords Mesh Terms:

KEYWORDS: Receptor, EphB2

MESH TERMS: metabolism

Chemical & Substance for Abstract: Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. Information

Substance Name: Amyloid Precursor Protein Secretases

Registry Number: EC 3.4.-

Grant and Affiliation Information for Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor.

AFFILIATION: Department of Psychiatry and Neuroscience, Mount Sinai School of Medicine New York University, New York, NY 10029, USA, and Institute for Molecular Cardiovascular Research, University Hospital Reinisch-West Faelische Technische Hochschule, Aachen, Germany

Country: United States

AGENCY: United States NINDS

GRANT: NS-47229

ACRONYM: NS

MEDLINETA: J Biol Chem

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