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Isoform-specific monoubiquitination, endocytosis, and degradation of alternatively spliced ErbB4 isoforms.


ABSTRACT: Endocytosis and subsequent lysosomal degradation serve as a well characterized mechanism to fine-tune and down-regulate EGFR signaling. However, other members of the EGFR/ErbB receptor family have been reported to be endocytosis-impaired. Here we demonstrate that endocytosis of ErbB4 is regulated in an isoform-specific manner: CYT-1 isoforms were efficiently endocytosed whereas CYT-2 isoforms were endocytosis-impaired. CYT-1 isoforms in endocytic vesicles colocalized with Rab5 and Rab7 indicating trafficking via early endosomes to late endosomal/lysosomal structures. A PPXY motif within the CYT-1-specific sequence that lacks from CYT-2 was necessary both for ubiquitination and endocytosis of CYT-1 isoforms and provided a binding site for a WW domain-containing ubiquitin ligase Itch. Itch catalyzed ubiquitination of ErbB4 CYT-1, promoted its localization into intracellular vesicles, and stimulated degradation of ErbB4 CYT-1. Dominant negative Itch suppressed ErbB4 CYT-1 endocytosis and degradation. These data indicate that ErbB4 isoforms differ in endocytosis and degradation by a mechanism mediated by CYT-1-specific PPXY motif interacting with a WW domain-containing E3 ubiquitin ligase.

SUBMITTER: Sundvall M 

PROVIDER: S-EPMC2393780 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Isoform-specific monoubiquitination, endocytosis, and degradation of alternatively spliced ErbB4 isoforms.

Sundvall Maria M   Korhonen Anna A   Paatero Ilkka I   Gaudio Eugenio E   Melino Gerry G   Croce Carlo M CM   Aqeilan Rami I RI   Elenius Klaus K  

Proceedings of the National Academy of Sciences of the United States of America 20080311 11


Endocytosis and subsequent lysosomal degradation serve as a well characterized mechanism to fine-tune and down-regulate EGFR signaling. However, other members of the EGFR/ErbB receptor family have been reported to be endocytosis-impaired. Here we demonstrate that endocytosis of ErbB4 is regulated in an isoform-specific manner: CYT-1 isoforms were efficiently endocytosed whereas CYT-2 isoforms were endocytosis-impaired. CYT-1 isoforms in endocytic vesicles colocalized with Rab5 and Rab7 indicatin  ...[more]

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