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

Maria Sundvall1, Anna Korhonen, Ilkka Paatero

  • 1MediCity Research Laboratory and Department of Medical Biochemistry and Molecular Biology, University of Turku, FIN-20520 Turku, Finland.

Proceedings of the National Academy of Sciences of the United States of America
|March 13, 2008
PubMed

Insights

ErbB4 receptor endocytosis is isoform-specific. CYT-1 ErbB4 isoforms are efficiently endocytosed and degraded, unlike CYT-2. A specific motif mediates this process via the Itch ubiquitin ligase.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Endocytosis and lysosomal degradation regulate Epidermal Growth Factor Receptor (EGFR) signaling.
  • Some EGFR/ErbB family members exhibit impaired endocytosis.

Purpose of the Study:

  • To investigate the isoform-specific regulation of ErbB4 endocytosis.
  • To elucidate the molecular mechanisms underlying differential ErbB4 endocytosis and degradation.

Main Methods:

  • Isoform-specific analysis of ErbB4 endocytosis.
  • Colocalization studies using Rab5 and Rab7 markers.
  • Investigation of the role of a PPXY motif and the Itch ubiquitin ligase.

Main Results:

  • ErbB4 CYT-1 isoforms are efficiently endocytosed, while CYT-2 isoforms are impaired.
  • A CYT-1-specific PPXY motif is essential for ubiquitination and endocytosis.
  • The E3 ubiquitin ligase Itch binds to the PPXY motif, catalyzing ubiquitination and promoting degradation of ErbB4 CYT-1.
  • Inhibition of Itch function impairs ErbB4 CYT-1 endocytosis and degradation.

Conclusions:

  • ErbB4 isoforms exhibit distinct endocytic and degradation pathways.
  • The CYT-1-specific PPXY motif and its interaction with Itch mediate ErbB4 endocytosis and lysosomal targeting.

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