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

249 Citations (Scopus)

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

Fingerprint

Presenilins
Amyloid Precursor Protein Secretases
Receptor Protein-Tyrosine Kinases
Neuregulins
Proteolysis
Amyloid beta-Protein Precursor
Substrates
Amino Acid Sequence
Assays
Membrane Proteins
Peptide Hydrolases
Cells
Membranes
Amino Acids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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

Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4. / Lee, Hahn Jun; Jung, Kwang Mook; Huang, Yang Z.; Bennett, Lori B.; Lee, Joanne S.; Mei, Lin; Kim, Tae Wan.

In: Journal of Biological Chemistry, Vol. 277, No. 8, 22.02.2002, p. 6318-6323.

Research output: Contribution to journalArticle

Lee, HJ, Jung, KM, Huang, YZ, Bennett, LB, Lee, JS, Mei, L & Kim, TW 2002, 'Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4', Journal of Biological Chemistry, vol. 277, no. 8, pp. 6318-6323. https://doi.org/10.1074/jbc.M110371200
Lee HJ, Jung KM, Huang YZ, Bennett LB, Lee JS, Mei L et al. Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4. Journal of Biological Chemistry. 2002 Feb 22;277(8):6318-6323. https://doi.org/10.1074/jbc.M110371200
Lee, Hahn Jun ; Jung, Kwang Mook ; Huang, Yang Z. ; Bennett, Lori B. ; Lee, Joanne S. ; Mei, Lin ; Kim, Tae Wan. / Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 8. pp. 6318-6323.
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