Dissociated presenilin-1 and TACE processing of ErbB4 in lung alveolar type II cell differentiation

作者：Fiaturi Najla^*; Ritzkat Anika; Dammann Christiane E L; Castellot John J; Nielsen Heber C

来源：Biochimica et Biophysica Acta-Molecular Cell Research, 2014, 1843(4): 797-805.

DOI：10.1016/j.bbamcr.2014.01.015

• ErbB receptor
• Gamma secretase
• Presenilin-1
• Neonatal lung
• Type II cell
• Surfactant protein

Neuregulin (NRG) stimulation of ErbB4 signaling is important for type II cell surfactant synthesis. ErbB4 may mediate gene expression via a non-canonical pathway involving enzymatic cleavage releasing its intracellular domain (4ICD) for nuclear trafficking and gene regulation. The accepted model for release of 4ICD is consecutive cleavage by Tumor necrosis factor alpha Converting Enzyme (TACE) and gamma-secretase enzymes. Here, we show that 4ICD mediates surfactant synthesis and its release by gamma-secretase is not dependent on previous TACE cleavage. We used siRNA to silence Presenilin-1 (PSEN-1) expression in a mouse lung type II epithelial cell line (MLE12 cells), and both siRNA knockdown and chemical inhibition of TACE. Knockdown of PSEN-1 significantly decreased baseline and NRG-stimulated surfactant phospholipid synthesis, expression of the surfactant proteins SP-B and SP-C, as well as 4ICD levels, with no change in ErbB4 ectodomain shedding. Neither siRNA knockdown nor chemical inhibition of TACE inhibited 4ICD release or surfactant synthesis. PSEN-1 cleavage of ErbB4 for noncanonical signaling through 4ICD release does not require prior cleavage by TACE.

• 出版日期2014-4