Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4

Hahn Jun Lee, Kwang Mook Jung, Yang Z. Huang, Lori B. Bennett, Joanne S. Lee, Lin Mei, Tae Wan Kim

Research output: Contribution to journalArticle

253 Scopus citations

Abstract

An unusual protease γ-secretase requires functional presenilins and cleaves substrates (e.g. amyloid β-protein precursor and Notch) with very loose amino acid sequence specificity within the transmembrane region. Here we report that ErbB4, a tyrosine kinase receptor for neuregulins, is a substrate for presenilin-dependent γ-secretase. Our studies show that constitutive ectodomain shedding of full-length ErbB4 yields the ∼80-kDa membrane-associated C-terminal fragment (B4-CTF). Subsequent intramembrane cleavage of the B4-CTF was inhibited in the cells devoid of functional presenilins or by treatment of cells with a γ-secretase inhibitor, leading to enhanced accumulation of B4-CTF. Furthermore, an in vitro γ-secretase assay demonstrated that the intracellular domain of ErbB4 (B4-ICD) was produced and subsequently released into the soluble fraction in a presenilin-dependent manner. We have also shown that ectopically expressed B4-ICD is localized to the nucleus, suggesting that the presenilin-dependent cleavage of ErbB4 generates the soluble B4-ICD that functions in the nucleus presumably at transcriptional level. Our study indicates that ErbB4 represents a first receptor tyrosine kinase that undergoes intramembrane proteolysis and may mediate a novel signaling function independent of its canonical role as a receptor tyrosine kinase. Our studies also support the idea that presenilins play a generic role in intramembrane cleavage of selected type I membrane proteins.

Original languageEnglish (US)
Pages (from-to)6318-6323
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number8
DOIs
StatePublished - Feb 22 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lee, H. J., Jung, K. M., Huang, Y. Z., Bennett, L. B., Lee, J. S., Mei, L., & Kim, T. W. (2002). Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4. Journal of Biological Chemistry, 277(8), 6318-6323. https://doi.org/10.1074/jbc.M110371200