@article{open469,
          volume = {43},
          number = {8},
           month = {August},
          author = {Eshu Singhal and Pradip Sen},
            note = {Copyrighy of this article belongs to Elsevier Science},
           title = {Hepatocyte growth factor-induced c-Src-phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway inhibits dendritic cell activation by blocking I{\ensuremath{\kappa}}B kinase activity.},
            year = {2011},
         journal = {The international journal of biochemistry \& cell biology},
           pages = {1134--46},
        keywords = {c-MET / dendritic cell / hepatocyte growth factor / NF-?B / signaling},
             url = {http://crdd.osdd.net/open/469/},
        abstract = {Hepatocyte growth factor modulates activation and antigen-presenting cell function of dendritic cells. However, the molecular basis for immunoregulation of dendritic cells by hepatocyte growth factor is undefined. In the current study, we demonstrate that hepatocyte growth factor exhibits inhibitory effect on dendritic cell activation by blocking I{\ensuremath{\kappa}}B kinase activity and subsequent nuclear factor-{\ensuremath{\kappa}}B activation. Inhibition of I{\ensuremath{\kappa}}B kinase is mediated by hepatocyte growth factor-induced activation of c-Src. Proximal signaling events induced in dendritic cells by hepatocyte growth factor include a physical association of c-Src with the hepatocyte growth factor receptor c-MET and concomitant activation of c-Src. Activation of c-Src in turn establishes a complex consisting of phosphatidylinositol 3-kinase and c-MET, and promotes downstream activation of the phosphatidylinositol 3-kinase/AKT pathway and mammalian target of rapamycin. Blocking activation of c-Src, phosphatidylinositol 3-kinase and mammalian target of rapamycin prevents hepatocyte growth factor-induced inhibition of I{\ensuremath{\kappa}}B kinase, nuclear factor-{\ensuremath{\kappa}}B and dendritic cell activation. Notably, hepatocyte growth factor-stimulated c-Src activation results in induction of phosphatidylinositol 3-kinase complexes p85{\ensuremath{\alpha}}/p110{\ensuremath{\alpha}} and p85{\ensuremath{\alpha}}/p110{\ensuremath{\delta}}, which is required for activation of mammalian target of rapamycin, and consequent inhibition of I{\ensuremath{\kappa}}B kinase and nuclear factor-{\ensuremath{\kappa}}B activation. Our findings, for the first time, have identified the c-Src-phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway that plays a pivotal role in mediating the inhibitory effects of hepatocyte growth factor on dendritic cell activation by blocking nuclear factor-{\ensuremath{\kappa}}B signaling.}
}