Presenilin-dependent γ-Secretase-like Intramembrane Cleavage of ErbB4*

By Hahn‐Jun Lee, Kwang-Mook Jung, Y. Z. Huang, Lori B. Bennett, Joanne S. Lee, L. Mei, Tae‐Wan Kim. Journal of Biological Chemistry, 2002

272 citations recorded by the source corpus.

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, anin 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.

Subfields: Cell Biology, Immunology and Allergy, Physiology

View Paper: https://www.semanticscholar.org/paper/26b5d5753a70d4351a2d3c452c925b22b77331d6

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In Physiology

Citations in the corpus

Neuregulin 1 in neural development, synaptic plasticity and schizophrenia (2008, background): “The remaining membrane-anchored 80 kDa fragment (that is, ErbB4-CTF) is further cleaved in its transmembrane domain by presenilin-dependent γ-secretase to release the ErbB4 intracellular domain (ErbB4-ICD”
Presenilins mediate a dual intramembranous γ‐secretase cleavage of Notch‐1 (2002, background): “…some of the proteolytically liberated ICDs translocate to the nucleus (Schroeter et al., 1998; Struhl and Adachi, 1998; Cao and SuÈdhof, 2001; Ni et al., 2001; Okamoto et al., 2001; Lee et al., 2002) where they do or may regulate transcription of target genes (reviewed in Steiner and Haass, 2001).”