Role of proneuregulin 1 cleavage and human epidermal growth factor receptor activation in hypertonic aquaporin induction.
Mammalian cells are confronted with changes in extracellular osmolality at various sites, including the aqueous layer above the lung epithelium. Hypertonic shock induces the activation of mitogen-activated protein kinases and the expression of a defined set of genes, including aquaporins. We investigated upstream components of the response to hypertonicity in lung epithelial cells and found that before extracellular signal-regulated kinase activation and aquaporin synthesis, the membrane-bound prohormone neuregulin 1-beta is cleaved and binds to human epidermal growth factor receptor 3 (HER3). The signaling is prevented by matrix metalloproteinase inhibition, inhibition of neuregulin 1-beta binding to HER3, and inhibition of HER tyrosine kinase activity. Inhibition of HER activation interferes with the hypertonic induction of two different aquaporins in three distinct cell lines of mouse and human origin. We propose that ligand-dependent HER activation constitutes a generalized signaling principle in the mammalian hypertonic stress response relevant to aquaporin expression.
Herrlich
Andreas
A
Renal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Leitch
Virginia
V
King
Landon S
LS
D000818:Animals; D051400:Aquaporin 3; D051402:Aquaporin 5; D020346:Aquaporins / Q000096:biosynthesis*; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D006982:Hypertonic Solutions; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000096:biosynthesis; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020890:Neuregulin-1; D009997:Osmotic Pressure; D011498:Protein Precursors / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism
D051400:Aquaporin 3; D051402:Aquaporin 5; D020346:Aquaporins; D066246:ErbB Receptors; D006982:Hypertonic Solutions; D008565:Membrane Proteins; D045726:Metalloproteases; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D011498:Protein Precursors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C496027:AQP3 protein, human; C496036:AQP5 protein, human; C496028:Aqp3 protein, mouse; C496038:Aqp5 protein, mouse; C094131:NRG1 protein, human; C490581:Nrg1 protein, mouse