Evidence for functional selectivity in TUDC- and norUDCA-induced signal transduction via α
ATP Binding Cassette Transporter, Subfamily B, Member 11
/ metabolism
Animals
Binding Sites
Cholagogues and Choleretics
/ chemistry
ErbB Receptors
/ metabolism
Integrin alpha5beta1
/ chemistry
Liver
/ drug effects
MAP Kinase Signaling System
Male
Molecular Docking Simulation
Protein Binding
Rats
Rats, Wistar
Taurochenodeoxycholic Acid
/ chemistry
Ursodeoxycholic Acid
/ chemistry
p38 Mitogen-Activated Protein Kinases
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
02 04 2020
02 04 2020
Historique:
received:
26
07
2018
accepted:
02
03
2020
entrez:
4
4
2020
pubmed:
4
4
2020
medline:
25
11
2020
Statut:
epublish
Résumé
Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor and has been described for G protein-coupled receptors. However, it has not yet been described for ligands interacting with integrins without αI domain. Here, we show by molecular dynamics simulations that four side chain-modified derivatives of tauroursodeoxycholic acid (TUDC), an agonist of α
Identifiants
pubmed: 32242141
doi: 10.1038/s41598-020-62326-y
pii: 10.1038/s41598-020-62326-y
pmc: PMC7118123
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B, Member 11
0
Abcb11 protein, rat
0
Cholagogues and Choleretics
0
Integrin alpha5beta1
0
Taurochenodeoxycholic Acid
516-35-8
ursodoxicoltaurine
60EUX8MN5X
Ursodeoxycholic Acid
724L30Y2QR
ErbB Receptors
EC 2.7.10.1
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5795Références
Urban, J. D. et al. Functional selectivity and classical concepts of quantitative pharmacology. J. Pharmacol. Exp. Ther. 320, 1–13, https://doi.org/10.1124/jpet.106.104463 (2007).
doi: 10.1124/jpet.106.104463
pubmed: 16803859
pmcid: 16803859
Violin, J. D. & Lefkowitz, R. J. Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28, 416–422, https://doi.org/10.1016/j.tips.2007.06.006 (2007).
doi: 10.1016/j.tips.2007.06.006
pubmed: 17644195
pmcid: 17644195
Simon, D. I. Opening the field of integrin biology to “biased agonism”. Circ. Res. 109, 1199–1201, https://doi.org/10.1161/CIRCRESAHA.111.257980 (2011).
doi: 10.1161/CIRCRESAHA.111.257980
pubmed: 22076504
pmcid: 22076504
Wolf, D. et al. Binding of CD40L to Mac-1’s I-domain involves the EQLKKSKTL motif and mediates leukocyte recruitment and atherosclerosis–but does not affect immunity and thrombosis in mice. Circ. Res. 109, 1269–1279, https://doi.org/10.1161/CIRCRESAHA.111.247684 (2011).
doi: 10.1161/CIRCRESAHA.111.247684
pubmed: 21998326
pmcid: 21998326
Gohlke, H., Schmitz, B., Sommerfeld, A., Reinehr, R. & Häussinger, D. α5β1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes. Hepatology 57, 1117–1129, https://doi.org/10.1002/hep.25992 (2013).
doi: 10.1002/hep.25992
pubmed: 22865233
pmcid: 22865233
Volpes, R., van den Oord, J. J. & Desmet, V. J. Integrins as differential cell lineage markers of primary liver tumors. Am. J. Pathol. 142, 1483–1492 (1993).
pubmed: 7684197
pmcid: 7684197
Häussinger, D. et al. Involvement of Integrins and Src in Tauroursodeoxycholate-Induced and Swelling-Induced Choleresis. Gastroenterology 124, 1476–1487, https://doi.org/10.1016/S0016-5085(03)00274-9 (2003).
doi: 10.1016/S0016-5085(03)00274-9
pubmed: 12730886
pmcid: 12730886
Schliess, F., Reissmann, R., Reinehr, R., vom Dahl, S. & Häussinger, D. Involvement of Integrins and Src in Insulin Signaling toward Autophagic Proteolysis in Rat Liver. J. Biol. Chem. 279, 21294–21301, https://doi.org/10.1074/jbc.M313901200 (2004).
doi: 10.1074/jbc.M313901200
pubmed: 14985360
pmcid: 14985360
vom Dahl, S. et al. Involvement of Integrins in Osmosensing and Signaling toward Autophagic Proteolysis in Rat Liver. J. Biol. Chem. 278, 27088–27095, https://doi.org/10.1074/jbc.M210699200 (2003).
doi: 10.1074/jbc.M210699200
pubmed: 12721289
pmcid: 12721289
Kurz, A. K., Graf, D., Schmitt, M., vom Dahl, S. & Häussinger, D. Tauroursodesoxycholate-Induced Choleresis Involves p38(MAPK) Activation and Translocation of the Bile Salt Export Pump in Rats. Gastroenterology 121, 407–419, gast.2001.26262 (2001).
Schmitt, M., Kubitz, R., Lizun, S., Wettstein, M. & Häussinger, D. Regulation of the Dynamic Localization of the Rat Bsep Gene-Encoded Bile Salt Export Pump by Anisoosmolarity. Hepatology 33, 509–518, https://doi.org/10.1053/jhep.2001.22648 (2001).
doi: 10.1053/jhep.2001.22648
Hanke, J. H. et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem. 271, 695–701 (1996).
doi: 10.1074/jbc.271.2.695
Beuers, U. et al. Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology 33, 1206–1216, https://doi.org/10.1053/jhep.2001.24034 (2001).
doi: 10.1053/jhep.2001.24034
Kubitz, R., D’Urso, D., Keppler, D. & Häussinger, D. Osmodependent Dynamic Localization of the Multidrug Resistance Protein 2 in the Rat Hepatocyte Canalicular Membrane. Gastroenterology 113, 1438–1442, gast.1997.v113.pm9352844 (1997).
Cantore, M., Reinehr, R., Sommerfeld, A., Becker, M. & Häussinger, D. The Src Family Kinase Fyn Mediates Hyperosmolarity-Induced Mrp2 and Bsep Retrieval from Canalicular Membrane. J. Biol. Chem. 286, 45014–45029, https://doi.org/10.1074/jbc.M111.292896 (2011).
doi: 10.1074/jbc.M111.292896
pubmed: 3247936
pmcid: 3247936
Sommerfeld, A., Mayer, P. G. K., Cantore, M. & Häussinger, D. Regulation of Plasma Membrane Localization of the Na+-Taurocholate Cotransporting Polypeptide (Ntcp) by Hyperosmolarity and Tauroursodeoxycholate. J. Biol. Chem. 290, 24237–24254, https://doi.org/10.1074/jbc.M115.666883 (2015).
doi: 10.1074/jbc.M115.666883
pubmed: 4591811
pmcid: 4591811
Schliess, F., Kurz, A. K., vom Dahl, S. & Häussinger, D. Mitogen-Activated Protein Kinases Mediate the Stimulation of Bile Acid Secretion by Tauroursodeoxycholate in Rat Liver. Gastroenterology 113, 1306–1314, https://doi.org/10.1053/gast.1997.v113.pm9322526 (1997).
doi: 10.1053/gast.1997.v113.pm9322526
Stieger, B. Recent insights into the function and regulation of the bile salt export pump (ABCB11). Curr. Opin. Lipidol. 20, 176–181, https://doi.org/10.1097/MOL.0b013e32832b677c (2009).
doi: 10.1097/MOL.0b013e32832b677c
Bochen, A. et al. Biselectivity of isoDGR peptides for fibronectin binding integrin subtypes alpha5beta1 and alphavbeta6: conformational control through flanking amino acids. J. Med. Chem. 56, 1509–1519, https://doi.org/10.1021/jm301221x (2013).
doi: 10.1021/jm301221x
Mas-Moruno, C., Rechenmacher, F. & Kessler, H. Cilengitide: the first anti-angiogenic small molecule drug candidate design, synthesis and clinical evaluation. Anticancer Agents Med. Chem. 10, 753–768 (2010).
doi: 10.2174/187152010794728639
Zhu, J. et al. Structure of a Complete Integrin Ectodomain in a Physiologic Resting State and Activation and Deactivation by Applied Forces. Mol. Cell 32, 849–861, https://doi.org/10.1016/j.molcel.2008.11.018 (2008).
doi: 10.1016/j.molcel.2008.11.018
pubmed: 2758073
pmcid: 2758073
Van Agthoven, J. F. et al. Structural basis for pure antagonism of integrin αVβ3 by a high-affinity form of fibronectin. Nat. Struct. Mol. Biol. 21, 383–388, https://doi.org/10.1038/nsmb.2797 (2014).
doi: 10.1038/nsmb.2797
pubmed: 4012256
pmcid: 4012256
Zhu, J., Zhu, J. & Springer, T. A. Complete integrin headpiece opening in eight steps. J. Cell Biol. 201, 1053–1068, https://doi.org/10.1083/jcb.201212037 (2013).
doi: 10.1083/jcb.201212037
pubmed: 3691460
pmcid: 3691460
Puklin-Faucher, E. & Vogel, V. Integrin activation dynamics between the RGD-binding site and the headpiece hinge. J. Biol. Chem. 284, 36557–36568, https://doi.org/10.1074/jbc.M109.041194 (2009).
doi: 10.1074/jbc.M109.041194
pubmed: 2794771
pmcid: 2794771
Puklin-Faucher, E., Gao, M., Schulten, K. & Vogel, V. How the headpiece hinge angle is opened: New insights into the dynamics of integrin activation. J. Cell Biol. 175, 349–360, https://doi.org/10.1083/jcb.200602071 (2006).
doi: 10.1083/jcb.200602071
pubmed: 2064575
pmcid: 2064575
Puklin-Faucher, E. & Sheetz, M. P. The mechanical integrin cycle. J. Cell Sci. 122, 179–186, https://doi.org/10.1242/jcs.042127 (2009).
doi: 10.1242/jcs.042127
Craig, D., Gao, M., Schulten, K. & Vogel, V. Structural insights into how the MIDAS ion stabilizes integrin binding to an RGD peptide under force. Structure 12, 2049–2058, https://doi.org/10.1016/j.str.2004.09.009 (2004).
doi: 10.1016/j.str.2004.09.009
Nakazawa, T., Hoshino, M., Hayakawa, T., Tanaka, A. & Ohiwa, T. Vasopressin reduces taurochenodeoxycholate-induced hepatotoxicity by lowering the hepatocyte taurochenodeoxycholate content. J. Hepatol. 25, 739–747, https://doi.org/10.1016/s0168-8278(96)80247-9 (1996).
doi: 10.1016/s0168-8278(96)80247-9
Agellon, L. B. & Torchia, E. C. Intracellular transport of bile acids. Biochim. Biophys. Acta 1486, 198–209, https://doi.org/10.1016/s1388-1981(00)00057-3 (2000).
doi: 10.1016/s1388-1981(00)00057-3
Setchell, K. D. et al. Bile acid concentrations in human and rat liver tissue and in hepatocyte nuclei. Gastroenterology 112, 226–235, https://doi.org/10.1016/s0016-5085(97)70239-7 (1997).
doi: 10.1016/s0016-5085(97)70239-7
pubmed: 8978363
pmcid: 8978363
vom Dahl, S., Hallbrucker, C., Lang, F. & Häussinger, D. Regulation of cell volume in the perfused rat liver by hormones. Biochem. J. 280(Pt 1), 105–109 (1991).
doi: 10.1042/bj2800105
König, J., Klatt, S., Dilger, K. & Fromm, M. F. Characterization of Ursodeoxycholic and Norursodeoxycholic Acid as Substrates of the Hepatic Uptake Transporters OATP1B1, OATP1B3, OATP2B1 and NTCP. Basic Clin. Pharmacol. Toxicol. 111, 81–86, https://doi.org/10.1111/j.1742-7843.2012.00865.x (2012).
doi: 10.1111/j.1742-7843.2012.00865.x
Ko, J. et al. Effects of side chain length on ionization behavior and transbilayer transport of unconjugated dihydroxy bile acids: a comparison of nor-chenodeoxycholic acid and chenodeoxycholic acid. J. Lipid Res. 35, 883–892 (1994).
pubmed: 8071610
pmcid: 8071610
Jedlitschky, G. et al. ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2. Biochem. J. 327(Pt 1), 305–310 (1997).
doi: 10.1042/bj3270305
Kamisako, T. et al. Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology 30, 485–490, https://doi.org/10.1002/hep.510300220 (1999).
doi: 10.1002/hep.510300220
Cui, Y. et al. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol. Pharmacol. 55, 929–937 (1999).
Denk, G. U. et al. Conjugation is essential for the anticholestatic effect of NorUrsodeoxycholic acid in taurolithocholic acid-induced cholestasis in rat liver. Hepatology 52, 1758–1768, https://doi.org/10.1002/hep.23911 (2010).
doi: 10.1002/hep.23911
Norris, R. P., Freudzon, M., Nikolaev, V. O. & Jaffe, L. A. Epidermal growth factor receptor kinase activity is required for gap junction closure and for part of the decrease in ovarian follicle cGMP in response to LH. Reproduction 140, 655–662, https://doi.org/10.1530/REP-10-0288 (2010).
doi: 10.1530/REP-10-0288
pubmed: 3119707
pmcid: 3119707
Rubio, I. et al. Ras activation in response to phorbol ester proceeds independently of the EGFR via an unconventional nucleotide-exchange factor system in COS-7 cells. Biochem. J 398, 243–256, https://doi.org/10.1042/BJ20060160 (2006).
doi: 10.1042/BJ20060160
pubmed: 1550314
pmcid: 1550314
Berger, C., Krengel, U., Stang, E., Moreno, E. & Madshus, I. H. Nimotuzumab and cetuximab block ligand-independent EGF receptor signaling efficiently at different concentrations. J. Immunother. 34, 550–555, https://doi.org/10.1097/CJI.0b013e31822a5ca6 (2011).
doi: 10.1097/CJI.0b013e31822a5ca6
Hofmann, A. F. et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology 42, 1391–1398, https://doi.org/10.1002/hep.20943 (2005).
doi: 10.1002/hep.20943
Trauner, M. et al. Potential of nor-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders. Dig. Dis. 33, 433–439, https://doi.org/10.1159/000371904 (2015).
doi: 10.1159/000371904
Kurz, A. K. et al. Phosphoinositide 3-kinase-dependent Ras activation by tauroursodesoxycholate in rat liver. Biochem. J. 350(Pt 1), 207–213, https://doi.org/10.1042/bj3500207 (2000).
doi: 10.1042/bj3500207
pubmed: 1221243
pmcid: 1221243
Kim, N.-G. & Gumbiner, B. M. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J. Cell Biol. 210, 503–515, https://doi.org/10.1083/jcb.201501025 (2015).
doi: 10.1083/jcb.201501025
pubmed: 4523609
pmcid: 4523609
Sampaio, C. et al. Signal Strength Dictates Phosphoinositide 3-Kinase Contribution to Ras/Extracellular Signal-Regulated Kinase 1 and 2 Activation via Differential Gab1/Shp2 Recruitment: Consequences for Resistance to Epidermal Growth Factor Receptor Inhibition. Mol. Cell. Biol. 28, 587–600, https://doi.org/10.1128/MCB.01318-07 (2008).
doi: 10.1128/MCB.01318-07
Clark, E. A. & Brugge, J. S. Integrins and signal transduction pathways: the road taken. Science 268, 233–239, https://doi.org/10.1126/science.7716514 (1995).
doi: 10.1126/science.7716514
García, A. J. & Boettiger, D. Integrin-fibronectin interactions at the cell-material interface: initial integrin binding and signaling. Biomaterials 20, 2427–2433, https://doi.org/10.1016/S0142-9612(99)00170-2 (1999).
doi: 10.1016/S0142-9612(99)00170-2
Mitra, S. K., Hanson, D. A. & Schlaepfer, D. D. Focal adhesion kinase: in command and control of cell motility. Nature Reviews Molecular Cell Biology 6, 56–68, https://doi.org/10.1038/nrm1549 (2005).
doi: 10.1038/nrm1549
Huveneers, S. & Danen, E. H. J. Adhesion signaling - crosstalk between integrins, Src and Rho. J. Cell Sci. 122, 1059–1069, https://doi.org/10.1242/jcs.039446 (2009).
doi: 10.1242/jcs.039446
pubmed: 19339545
pmcid: 19339545
Shah, B. H., Neithardt, A., Chu, D. B., Shah, F. B. & Catt, K. J. Role of EGF receptor transactivation in phosphoinositide 3-kinase-dependent activation of MAP kinase by GPCRs. J. Cell. Physiol. 206, 47–57, https://doi.org/10.1002/jcp.20423 (2006).
doi: 10.1002/jcp.20423
Yoon, Y. B. et al. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology 90, 837–852 (1986).
doi: 10.1016/0016-5085(86)90859-0
Fickert, P. et al. 24-norUrsodeoxycholic Acid is Superior to Ursodeoxycholic Acid in the Treatment of Sclerosing Cholangitis in Mdr2 (Abcb4) Knockout Mice. Gastroenterology 130, 465–481, https://doi.org/10.1053/j.gastro.2005.10.018 (2006).
doi: 10.1053/j.gastro.2005.10.018
Noe, J., Stieger, B. & Meier, P. J. Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology 123, 1659–1666, https://doi.org/10.1053/gast.2002.36587 (2002).
doi: 10.1053/gast.2002.36587
Stieger, B. et al. In situ localization of the hepatocytic Na+/Taurocholate cotransporting polypeptide in rat liver. Gastroenterology 107, 1781–1787, https://doi.org/10.1016/0016-5085(94)90821-4 (1994).
doi: 10.1016/0016-5085(94)90821-4
Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graphics 14(33-38), 27–38, https://doi.org/10.1016/0263-7855(96)00018-5 (1996).
doi: 10.1016/0263-7855(96)00018-5
Xiao, T., Takagi, J., Coller, B. S., Wang, J.-H. & Springer, T. A. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432, 59–67, https://doi.org/10.1038/nature02976 (2004).
doi: 10.1038/nature02976
pubmed: 4372090
pmcid: 4372090
Roe, D. R. & Cheatham, T. E. III. PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. J. Chem. Theory Comput. 9, 3084–3095, https://doi.org/10.1021/ct400341p (2013).
doi: 10.1021/ct400341p
Sies, H. The use of perfusion of liver and other organs for the study of microsomal electron-transport and cytochrome P-450 systems. Methods Enzymol. 52, 48–59, https://doi.org/10.1016/S0076-6879(78)52005-3 (1978).
doi: 10.1016/S0076-6879(78)52005-3
R: A language and environment for statistical computing (R Foundation for Statistical Computing, Vienna, Austria, 2010).