Presenilin-dependent γ-Secretase Processing Regulates Multiple ERBB4/HER4 Activities

Transmembrane receptors typically transmit cellular signals following growth factor stimulation by coupling to and activating downstream signaling cascades. Reports of proteolytic processing of cell surface receptors to release an intracellular domain (ICD) has raised the possibility of novel signal...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2005-05, Vol.280 (20), p.19777-19783
Main Authors: Vidal, Gregory A., Naresh, Anjali, Marrero, Luis, Jones, Frank E.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Substitution
Amyloid Precursor Protein Secretases
Animals
Aspartic Acid Endopeptidases
Binding Sites - genetics
Caseins - genetics
Cell Line
Chlorocebus aethiops
COS Cells
DNA-Binding Proteins - metabolism
Endopeptidases - metabolism
ErbB Receptors - chemistry
ErbB Receptors - genetics
ErbB Receptors - metabolism
Humans
Membrane Proteins - metabolism
Milk Proteins - metabolism
Models, Biological
Molecular Sequence Data
Mutagenesis, Site-Directed
Presenilin-1
Promoter Regions, Genetic
Protein Processing, Post-Translational
Receptor, ErbB-4
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Signal Transduction
STAT5 Transcription Factor
Trans-Activators - metabolism
Transfection
Tumor Suppressor Proteins
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Transmembrane receptors typically transmit cellular signals following growth factor stimulation by coupling to and activating downstream signaling cascades. Reports of proteolytic processing of cell surface receptors to release an intracellular domain (ICD) has raised the possibility of novel signaling mechanisms directly mediated by the receptor ICD. The receptor tyrosine kinase ERBB4/HER4 (referred to here as ERBB4) undergoes sequential processing by tumor necrosis factor-α converting enzyme and presenilin-dependent γ-secretase to release the ERBB4 ICD (4ICD). Our recent data suggests that regulation of gene expression by the ERBB4 nuclear protein and the proapoptotic activity of ERBB4 involves the γ-secretase release of 4ICD. To determine the role γ-secretase processing plays in ERBB4 signaling, we generated an ERBB4 allele with the transmembrane residue substitution V673I (ERBB4-V673I). We demonstrate that ERBB4-V673I fails to undergo processing by γ-secretase but retains normal cell surface signaling activity. In contrast to wild-type ERBB4, however, ERBB4-V673I was excluded from the nuclei of transfected cells and failed to activate STAT5A stimulation of the β-casein promoter. These results support the contention that γ-secretase processing of ERBB4 is necessary to release a functional 4ICD nuclear protein which directly regulates gene expression. We also demonstrate that 4ICD failed to accumulate within mitochondria of ERBB4-V673I transfected cells and the potent proapoptotic activity of ERBB4 was completely abolished in cells expressing ERBB4-V673I. Our results provide the first formal demonstration that proteolytic processing of ERBB4 is a critical event regulating multiple receptor signaling activities.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M412457200