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Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities

Gregory A Vidal1, Anjali Naresh, Luis Marrero

  • 1Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699, USA.

The Journal of Biological Chemistry
|March 5, 2005
PubMed

Insights

Proteolytic processing of ERBB4 receptor releases its intracellular domain (4ICD), which is essential for nuclear gene regulation and proapoptotic activity. This processing is critical for ERBB4 signaling functions.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Receptor tyrosine kinases

Background:

  • Transmembrane receptors transmit signals via downstream cascades.
  • Proteolytic processing of receptors releases intracellular domains (ICDs), suggesting novel signaling pathways.
  • ERBB4 (also known as HER4) undergoes sequential processing by TNF-alpha converting enzyme and gamma-secretase to release its ICD (4ICD).

Purpose of the Study:

  • To investigate the role of gamma-secretase processing in ERBB4 signaling.
  • To determine if gamma-secretase-mediated release of 4ICD is necessary for ERBB4's nuclear and proapoptotic functions.

Main Methods:

  • Generated an ERBB4 allele (ERBB4-V673I) with a transmembrane residue substitution to block gamma-secretase processing.
  • Assessed cell surface signaling activity of wild-type ERBB4 and ERBB4-V673I.
  • Examined nuclear translocation of ERBB4 and its ICD.
  • Evaluated STAT5A-mediated beta-casein promoter activation.
  • Assessed mitochondrial accumulation of 4ICD and proapoptotic activity.

Main Results:

  • ERBB4-V673I failed to undergo gamma-secretase processing but maintained normal cell surface signaling.
  • ERBB4-V673I was excluded from the nucleus and did not activate STAT5A-mediated gene expression.
  • The proapoptotic activity of ERBB4 was abolished in cells expressing ERBB4-V673I.
  • 4ICD did not accumulate in mitochondria of ERBB4-V673I transfected cells.

Conclusions:

  • Gamma-secretase processing of ERBB4 is essential for releasing a functional 4ICD nuclear protein that directly regulates gene expression.
  • Proteolytic processing of ERBB4 is a critical event regulating its multiple signaling activities, including nuclear translocation and apoptosis.
  • This study provides the first formal evidence linking ERBB4 proteolytic processing to its diverse cellular functions.

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