Presenilin-1 processing of ErbB4 in fetal type II cells is necessary for control of fetal lung maturation

Abstract

Maturation of pulmonary fetal type II cells to initiate adequate surfactant production is crucial for postnatal respiratory function. Little is known about specific mechanisms of signal transduction controlling type II cell maturation. The ErbB4 receptor and its ligand neuregulin (NRG) are critical for lung development. ErbB4 is cleaved at the cell membrane by the γ-secretase enzyme complex whose active component is either presenilin-1 (PSEN-1) or presenilin-2. ErbB4 cleavage releases the 80 kDa intracellular domain (4ICD) which associates with chaperone proteins such as YAP (Yes associated protein) and translocates to the nucleus to regulate gene expression. We hypothesized that PSEN-1 and YAP have a development-specific expression in fetal type II cells and are important for ErbB4 signaling in surfactant production. In primary fetal mouse E16, E17, and E18 type II cells, PSEN-1 and YAP expression increased at E17 and E18 over E16. Subcellular fractionation showed a strong cytosolic and a weaker membrane location of both PSEN-1 and YAP. This was enhanced by NRG stimulation. Co-immunoprecipitations showed ErbB4 associated separately with PSEN-1 and with YAP. Their association, phosphorylation and co-localization were induced by NRG. Confocal immunofluorescence and nuclear fractionation confirmed these associations in a time-dependent manner after NRG stimulation. Primary ErbB4-deleted E17 type II cells were transfected with a mutant ErbB4 lacking the γ-secretase binding site. When compared to transfection with wild type ErbB4, the stimulatory effect of NRG on surfactant protein mRNA expression was lost. We conclude that PSEN-1 and YAP have crucial roles in ErbB4 signal transduction during type II cell maturation.

Receptor Tyrosine Kinases in the Nucleus

“…Interestingly, there is a genetic correlation between ErbB-4 and schizophrenia (Pan et al 2011) and the involvement of the ICD fragment in controlling gene expression in relevant cell types has been reported (Wong and Weickert 2009;Allison et al 2011). Also, the maturation of fetal lung cells is reported to be dependent on secretase processing of ErbB-4 and ICD association with the transcription factors YAP (Hoeing et al 2011), STAT 5a (Zscheppang et al 2011a), and ERb (Zscheppang et al 2011b). It is suggested that these interactions allow ErbB-4 to regulate transcription of surfactant protein B and thereby promote lung maturation.…”

TACE in perinatal mouse lung epithelial cells promotes lung saccular formation

“…One potential candidate that is cleaved by TACE is ErbB4. One of the ErbB4 isoforms is subjected to sequential TACE and Presenilin-1 cleavage (7). The released intracellular domain of ErbB4 has been shown to act as a cofactor for Sftpb transcription and type II cell differentiation (12,27).…”

What is the identity of fibroblast-pneumocyte factor?

“…This phosphorylation activates intracellular signaling pathways such as the phosphatidylinositol-3-kinase/Akt pathway to ultimately influence gene expression (70, 76, 84). Alternatively, ErbB4 may undergo proteolytic processing involving two sequential cleavage processes, first by the transmembrane metalloprotease tumor necrosis factor-α converting enzyme (TACE); and second by the enzyme γ-secretase, a complex of four proteins in which the enzymatic component is either presenilin-1 or presenilin-2 (85, 86). Presenilins are crucial for normal lung development (87).…”