Non-classical export of epimorphin and its adhesion to alphav-integrin in regulation of epithelial morphogenesis.
Epimorphin (also known as syntaxin 2) acts as an epithelial morphogen when secreted by stromal cells of the mammary gland, lung, liver, colon, pancreas and other tissues, but the same molecule functions within the cell to mediate membrane fusion. How this molecule, which lacks a signal sequence and contains a transmembrane domain at the C-terminus, translocates across the plasma membrane and is secreted to become a morphogen, and how it initiates morphogenic events is not clear. Here, we show that epimorphin is secreted through a non-classical mechanism, similar to that previously described for secretion of the leaderless protein FGF1, and we identify the key molecular elements responsible for translocation and secretion from the cell. We also show that secreted epimorphin binds to alphav-integrin-containing receptors on target epithelial cells, leading to activation of specific downstream signaling pathways and induction of epithelial morphogenesis. These findings provide key insight into how epimorphin functions as an epithelial morphogen.
Hirai
Yohei
Y
Department of Morphoregulation, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. hirai-yohei@frontier.kyoto-u.ac.jp
Nelson
Celeste M
CM
Yamazaki
Kyoko
K
Takebe
Kyoko
K
Przybylo
Jennifer
J
Madden
Benjamin
B
Radisky
Derek C
DC
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D004848:Epithelium / Q000196:embryology* / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism*; D008561:Membrane Fusion / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
C504582:Epim protein, mouse; D039564:Integrin alphaV; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases