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J. Biol. Chem., Vol. 282, Issue 22, 16155-16163, June 1, 2007

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Ligand Binding and Calcium Influx Induce Distinct Ectodomain/-Secretase-processing Pathways of EphB2 Receptor^*

Claudia Litterst, Anastasios Georgakopoulos, Junichi Shioi, Enrico Ghersi, Thomas Wisniewski, Rong Wang^¶, Andreas Ludwig^||, and Nikolaos K. Robakis¹

From the Center for Neurodegeneration, Departments of Psychiatry and Neuroscience and ^¶Department of Human Genetics, Mount Sinai School of Medicine New York University (NYU), New York, New York 10029, the Department of Neurology, NYU Medical Center New York, New York 10016, and the ^||Institute for Molecular Cardiovascular Research, University Hospital Reinisch-West Faelische Technische Hochschule, Aachen 52056, Germany

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 -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.

Received for publication, December 14, 2006 , and in revised form, April 6, 2007.

^* This work was supported by National Institutes of Health Grants AG-17926, AG-08200, and NS-47229 (to N. K. R.), AG-05138 (to A. G.), and CA088325 (to R. W.) and by the German Research Foundation (Deutsche Forschungsgemeinschaft). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Mount Sinai School of Medicine, New York University, One Gustave Levy Place, Box 1229. New York, NY 10029. Tel.: 212-241-9380; Fax: 212-831-1947; E-mail: nikos.robakis{at}mssm.edu.

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