Role of the ErbB-4 Carboxyl Terminus in γ-Secretase Cleavage
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 p...
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Published in | The Journal of biological chemistry Vol. 278; no. 7; p. 4561 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
14.02.2003
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Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M210504200 |