TY  - JOUR
AU  - vom Dahl, S.
AU  - Schliess, F.
AU  - Reissmann, R.
AU  - Görg, B.
AU  - Weiergräber, O.
AU  - Kocalkova, M.
AU  - Dombrowski, F.
AU  - Häussinger, D.
TI  - Involvement of integrins in osmosensing and signaling towards autophagic proteolysis in rat liver
JO  - The journal of biological chemistry
VL  - 278
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.
M1  - PreJuSER-32540
SP  - 27088 - 27095
PY  - 2003
N1  - Record converted from VDB: 12.11.2012
AB  - Inhibition of autophagic proteolysis by hypoosmotic or amino acid-induced hepatocyte swelling requires osmosignaling toward p38MAPK; however, the upstream osmosensing and signaling events are unknown. These were studied in the intact perfused rat liver with a preserved in situ environment of hepatocytes. It was found that hypoosmotic hepatocyte swelling led to an activation of Src (but not FAK), Erks, and p38MAPK, which was prevented by the integrin inhibitory hexapeptide GRGDSP, but not its inactive analogue GRGESP. Src inhibition by PP-2 prevented hypoosmotic MAP kinase activation, indicating that the integrin/Src system is located upstream in the osmosignaling toward p38MAPK and Erks. Inhibition of the integrin/Src system by the RGD motif-containing peptide or PP-2 also prevented the inhibition of proteolysis and the decrease in autophagic vacuole volume, which is otherwise observed in response to hypoosmotic or glutamine/glycine-induced hepatocyte swelling. These inhibitors, however, did not affect swelling-independent proteolysis inhibition by phenylalanine. In line with a role of p38MAPK in triggering the volume regulatory decrease (RVD), PP-2 and the RGD peptide blunted RVD in response to hypoosmotic cell swelling. The data identify integrins and Src as upstream events in the osmosignaling toward MAP kinases, proteolysis, and RVD. They further point to a role of integrins as osmo- and mechanosensors in the intact liver, which may provide a link between cell volume and cell function.
KW  - Animals
KW  - Autophagy
KW  - Cell Size: drug effects
KW  - Cell Size: physiology
KW  - Cells, Cultured
KW  - Hepatocytes: cytology
KW  - Hepatocytes: drug effects
KW  - Hepatocytes: physiology
KW  - Integrins: antagonists & inhibitors
KW  - Integrins: physiology
KW  - Liver: drug effects
KW  - Liver: physiology
KW  - Liver: ultrastructure
KW  - MAP Kinase Signaling System
KW  - Male
KW  - Mitogen-Activated Protein Kinases: metabolism
KW  - Models, Biological
KW  - Oligopeptides: pharmacology
KW  - Perfusion
KW  - Rats
KW  - Rats, Wistar
KW  - Signal Transduction
KW  - Water-Electrolyte Balance: physiology
KW  - p38 Mitogen-Activated Protein Kinases
KW  - src-Family Kinases: antagonists & inhibitors
KW  - src-Family Kinases: metabolism
KW  - Integrins (NLM Chemicals)
KW  - Oligopeptides (NLM Chemicals)
KW  - glycyl-arginyl-glycyl-aspartyl-seryl-proline (NLM Chemicals)
KW  - arginyl-glycyl-aspartic acid (NLM Chemicals)
KW  - glycyl-arginyl-glycyl-glutamyl-seryl-proline (NLM Chemicals)
KW  - src-Family Kinases (NLM Chemicals)
KW  - Mitogen-Activated Protein Kinases (NLM Chemicals)
KW  - p38 Mitogen-Activated Protein Kinases (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:12721289
UR  - <Go to ISI:>//WOS:000184155700102
DO  - DOI:10.1074/jbc.M210699200
UR  - https://juser.fz-juelich.de/record/32540
ER  -