Quantity control of the ErbB3 receptor tyrosine kinase at the endoplasmic reticulum

William H D Fry, Catalina Simion, Colleen A Sweeney, Kermit L Carraway

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The ErbB3 receptor tyrosine kinase contributes to a variety of developmental processes, and its overexpres- sion and aberrant activation promote tumor progression and therapeutic resistance. Accumulating evidence suggests that tumor overexpression may be mediated by the loss of posttranscriptional negative regulatory mechanisms, such as protein degradation, that normally keep receptor levels in check. Our previous studies indicate that the RING finger E3 ubiquitin ligase Nrdp1, a protein lost in breast and other tumor types, suppresses ErbB3 levels by mediating ligand-independent receptor ubiquitination and degradation. Here we demonstrate that Nrdp1 preferentially associates with the nascent form of ErbB3 to accelerate its degradation, and we show that the two proteins colocalize at the endoplasmic reticulum (ER). Blocking the exit of ErbB3 from the ER does not affect the ability of Nrdp1 to mediate receptor ubiquitination or degradation, while functional disruption of the conserved ER-associated degradation (ERAD) pathway ATPase VCP/p97 leads to the Nrdp1-dependent accumulation of ubiquitinated ErbB3 but blocks receptor degradation. Further evidence indicates that the ErbB3 targeted by Nrdp1 for degradation is properly folded and fully functional. Collectively, these observations point to a novel mechanism of receptor tyrosine kinase quantity control wherein steady- state levels of signaling-competent receptor are dictated by an ER-localized degradation pathway.

Original languageEnglish (US)
Pages (from-to)3009-3018
Number of pages10
JournalMolecular and Cellular Biology
Volume31
Issue number14
DOIs
StatePublished - Jul 2011

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Receptor Protein-Tyrosine Kinases
Endoplasmic Reticulum
Ubiquitination
Endoplasmic Reticulum-Associated Degradation
Ubiquitin-Protein Ligases
Proteolysis
Neoplasms
Proteins
Breast Neoplasms
Ligands
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Quantity control of the ErbB3 receptor tyrosine kinase at the endoplasmic reticulum. / Fry, William H D; Simion, Catalina; Sweeney, Colleen A; Carraway, Kermit L.

In: Molecular and Cellular Biology, Vol. 31, No. 14, 07.2011, p. 3009-3018.

Research output: Contribution to journalArticle

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