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

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.