Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis.
OBJECTIVE
Stimulation of canalicular secretion by tauroursodeoxycholate (TUDC) involves dual activation of p38 mitogen-activated protein kinase (p38(MAPK)) and extracellular signal-regulated kinase (ERK). This study investigates the sensing and upstream signaling events of TUDC-induced choleresis.


METHODS
TUDC and hypo-osmolarity effects on protein kinase activities and taurocholate excretion were studied in perfused rat liver.


RESULTS
TUDC induced a rapid activation of focal adhesion kinase (FAK) and Src, as shown by an increase in Y418 phosphorylation and a decrease in Y529 phosphorylation of Src. Inhibition of Src by PP-2 abolished the TUDC-induced activation of p38(MAPK) but not of FAK and ERKs. An integrin-inhibitory peptide with an RGD motif blocked TUDC-induced FAK, Src, ERK, and p38(MAPK) activation, suggesting that integrin signaling toward FAK/Src is required for TUDC-induced MAPK activation. The RGD peptide and PP-2 also abolished the stimulation of taurocholate excretion in perfused rat liver in response to TUDC. Integrin-dependent Src activation was also identified as an upstream event in hypo-osmotic signaling toward MAPKs and choleresis.


CONCLUSIONS
TUDC-induced stimulation of canalicular taurocholate excretion involves integrin sensing, FAK, and Src activation as upstream events for dual MAPK activation. Integrins may also represent one long-searched sensor for cell hydration changes in response to hypo-osmolarity.
Häussinger
Dieter
D
Department of Gastroenterology, Hepatology and Infectology, Universitätsklinikum Düsseldorf, Germany. haeussin@uni-duesseldorf.de
Kurz
Anna Kordelia
AK
Wettstein
Matthias
M
Graf
Dirk
D
Vom Dahl
Stephan
S
Schliess
Freimut
F
D000818:Animals; D001648:Bile Canaliculi / Q000378:metabolism*; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016023:Integrins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014882:Water-Electrolyte Balance / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
D002756:Cholagogues and Choleretics; D016023:Integrins; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D019061:src-Family Kinases