Protection from pancreatitis by the zymogen granule membrane protein integral membrane-associated protein-1.
Pancreatitis is a common disease with substantial morbidity and mortality. To better understand the mechanisms conferring sensitivity or resistance to pancreatitis, we have initiated the analysis of novel acinar cell proteins. Integral membrane-associated protein-1 (Itmap1) is a CUB (complement subcomponents C1r/C1s, sea urchin Uegf protein, bone morphogenetic protein-1) and zona pellucida (ZP) domain-containing protein we find prominently expressed in pancreatic acinar cells. Within the acinar cell, Itmap1 localizes to zymogen granule membranes. Although roles in epithelial polarity, granule assembly, and mucosal protection have been postulated for CUB/ZP proteins, in vivo functions for these molecules have not been proven. To determine the function of Itmap1, we generated Itmap1-deficient mice. Itmap1(-/-) mice demonstrate increased severity of secretagogue- and diet-induced pancreatitis in comparison to Itmap1(+/+) mice. In contrast to previous animal models exhibiting altered severity of pancreatitis, Itmap1 deficiency results in impaired activation of trypsin, an enzyme believed critical for initiating a cascade of digestive zymogen activation during pancreatitis. Itmap1 deficiency does not alter zymogen granule size, appearance, or the composition of zymogen granule contents. Our results demonstrate that Itmap1 plays an essential role in trypsinogen activation and that both impaired and augmented trypsinogen activation can be associated with increased severity of pancreatitis.
Imamura
Takuji
T
Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
Asada
Minoru
M
Vogt
Sherri K
SK
Rudnick
David A
DA
Lowe
Mark E
ME
Muglia
Louis J
LJ
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D000818:Animals; D004032:Diet; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010195:Pancreatitis / Q000453:epidemiology / Q000517:prevention & control*
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; C120083:ITM2B protein, human; C492300:Itm2b protein, mouse; C471299:Itmap2b protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins