Role of the ErbB-4 Carboxyl Terminus in γ-Secretase Cleavage

• Published in: The Journal of biological chemistry Vol. 278; no. 7; p. 4561
• Main Authors: Chang-Yuan Ni, Hongping Yuan, Graham Carpenter
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 14.02.2003
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M210504200

The ErbB-4 receptor tyrosine kinase has a PDZ domain recognition motif at its carboxyl terminus. The first step in ErbB-4 proteolytic processing is a metalloprotease-dependent cleavage of the receptor ectodomain, which is not influenced by deletion of this motif. Metalloprotease cleavage of ErbB-4 produces a membrane-associated 80-kDa fragment that is a substrate for subsequent γ-secretase cleavage, which releases the cytoplasmic domain from the membrane and allows nuclear translocation of this fragment. Deletion of the PDZ domain recognition motif does abrogate the γ-secretase cleavage of ErbB-4. The wild-type 80-kDa ErbB-4 fragment forms an association complex with presenilin, thought to be the catalytic moiety of γ-secretase activity. However, this association is significantly impaired by loss of the PDZ domain recognition motif from ErbB-4. Deletion of this ErbB-4 motif prevents the nuclear localization of the ErbB-4 cytoplasmic domain. Data also show that the basal cleavage of wild-type ErbB-4 by this proteolytic system can produce a sufficient level of ErbB-4 processing to negatively influence cell growth and that loss of the PDZ domain recognition motif abrogates this response.