Dissociated presenilin-1 and TACE processing of ErbB4 in lung alveolar type II cell differentiation.
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 γ-secretase enzymes. Here, we show that 4ICD mediates surfactant synthesis and its release by γ-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 non-canonical signaling through 4ICD release does not require prior cleavage by TACE.
Program in Pharmacology and Experimental Therapeutics, Department of Integrative Physiology and Pathobiology, Sackler School of Graduate Biomedical Studies, Tufts University, Boston, MA 02111, USA. Electronic address: najfit@gmail.com.
Najla
N
Fiaturi
Department of Pediatrics, Tufts Medical Center, Boston, MA 02111 USA; Hannover Medical School, Hannover, Germany. Electronic address: anika.ritzkat@gmx.de.
Anika
A
Ritzkat
Department of Pediatrics, Tufts Medical Center, Boston, MA 02111 USA; Hannover Medical School, Hannover, Germany; Graduate Program in Cell, Molecular and Developmental Biology, Department of Integrative Physiology and Pathobiology, Sackler School of Graduate Biomedical Studies, Tufts University, Boston, MA 02111, USA. Electronic address: cdammann@tuftsmedicalcenter.org.
Christiane E L
CE
Dammann
Program in Pharmacology and Experimental Therapeutics, Department of Integrative Physiology and Pathobiology, Sackler School of Graduate Biomedical Studies, Tufts University, Boston, MA 02111, USA; Graduate Program in Cell, Molecular and Developmental Biology, Department of Integrative Physiology and Pathobiology, Sackler School of Graduate Biomedical Studies, Tufts University, Boston, MA 02111, USA. Electronic address: john.castellot@tufts.edu.
John J
JJ
Castellot
Department of Pediatrics, Tufts Medical Center, Boston, MA 02111 USA; Graduate Program in Cell, Molecular and Developmental Biology, Department of Integrative Physiology and Pathobiology, Sackler School of Graduate Biomedical Studies, Tufts University, Boston, MA 02111, USA. Electronic address: heber.nielsen@tufts.edu.
Heber C
HC
Nielsen
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D000072198:ADAM17 Protein; D056809:Alveolar Epithelial Cells / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D020890:Neuregulin-1 / Q000235:genetics; D053764:Presenilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism; D034741:RNA, Small Interfering; D066247:Receptor, ErbB-4
D020890:Neuregulin-1; D053764:Presenilin-1; D011663:Pulmonary Surfactants; D034741:RNA, Small Interfering; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
ErbB receptor; Gamma secretase; Neonatal lung; Presenilin-1; Surfactant protein; Type II cell