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

Maria Sundvall, Anna Korhonen, Ilkka Paatero, Eugenio Gaudio, Gerry Melino, Carlo M. Croce, Rami I. Aqeilan, Klaus Elenius

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)4162-4167
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number11
DOIs
Publication statusPublished - Mar 18 2008

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Endocytosis
Protein Isoforms
Ubiquitination
Transport Vesicles
Ubiquitin-Protein Ligases
Endosomes
Ligases
Ubiquitin
Down-Regulation
Binding Sites

Keywords

  • AIP4
  • Itch
  • Ubiquitination
  • WW domain

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Isoform-specific monoubiquitination, endocytosis, and degradation of alternatively spliced ErbB4 isoforms. / Sundvall, Maria; Korhonen, Anna; Paatero, Ilkka; Gaudio, Eugenio; Melino, Gerry; Croce, Carlo M.; Aqeilan, Rami I.; Elenius, Klaus.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 11, 18.03.2008, p. 4162-4167.

Research output: Contribution to journalArticle

Sundvall, Maria ; Korhonen, Anna ; Paatero, Ilkka ; Gaudio, Eugenio ; Melino, Gerry ; Croce, Carlo M. ; Aqeilan, Rami I. ; Elenius, Klaus. / Isoform-specific monoubiquitination, endocytosis, and degradation of alternatively spliced ErbB4 isoforms. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 11. pp. 4162-4167.
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