Hepatocyte Growth Factor Suppresses Proinflammatory NFkappaB Activation through GSK3beta Inactivation in Renal Tubular Epithelial Cells

@article{citeulike:2628641, abstract = {Activation of NF{kappa}B is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor (HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NF{kappa}B activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3 suppresses NF{kappa}B p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3 consensus motif and could be directly phosphorylated by GSK3 both in vivo and in vitro, signifying Ser-468 of RelA/p65 as a putative substrate for GSK3. In addition, the C terminus of RelA/p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3. Moreover, this domain was required for efficient phosphorylation of Ser-468 and was indispensable for the physical interaction between RelA/p65 and GSK3. HGF substantially intercepted this interaction by inactivating GSK3. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NF{kappa}B-dependent genes. Diminished phosphorylation at Ser-468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NF{kappa}B activation was consistently mimicked by a selective GSK3 inhibitor or GSK3 knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3. Collectively, our findings suggest that HGF has a potent suppressive effect on NF{kappa}B activation, which is mediated by GSK3, an important signaling transducer controlling RelA/p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease. 10.1074/jbc.M710396200}, author = {Gong, Rujun and Rifai, Abdalla and Ge, Yan and Chen, Shan and Dworkin, Lance D. }, citeulike-article-id = {2628641}, doi = {10.1074/jbc.M710396200}, journal = {J. Biol. Chem.}, month = {March}, number = {12}, pages = {7401--7410}, posted-at = {2008-04-04 07:16:44}, priority = {2}, title = {Hepatocyte Growth Factor Suppresses Proinflammatory NF{kappa}B Activation through GSK3{beta} Inactivation in Renal Tubular Epithelial Cells}, url = {http://dx.doi.org/10.1074/jbc.M710396200}, volume = {283}, year = {2008} }

TY - JOUR ID - citeulike:2628641 L3 - citeulike-article-id:2628641 TI - Hepatocyte Growth Factor Suppresses Proinflammatory NF{kappa}B Activation through GSK3{beta} Inactivation in Renal Tubular Epithelial Cells JF - J. Biol. Chem. VL - 283 IS - 12 SP - 7401 EP - 7410 N2 - Activation of NF{kappa}B is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor (HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NF{kappa}B activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3 suppresses NF{kappa}B p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3 consensus motif and could be directly phosphorylated by GSK3 both in vivo and in vitro, signifying Ser-468 of RelA/p65 as a putative substrate for GSK3. In addition, the C terminus of RelA/p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3. Moreover, this domain was required for efficient phosphorylation of Ser-468 and was indispensable for the physical interaction between RelA/p65 and GSK3. HGF substantially intercepted this interaction by inactivating GSK3. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NF{kappa}B-dependent genes. Diminished phosphorylation at Ser-468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NF{kappa}B activation was consistently mimicked by a selective GSK3 inhibitor or GSK3 knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3. Collectively, our findings suggest that HGF has a potent suppressive effect on NF{kappa}B activation, which is mediated by GSK3, an important signaling transducer controlling RelA/p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease. 10.1074/jbc.M710396200 AU - Gong, Rujun AU - Rifai, Abdalla AU - Ge, Yan AU - Chen, Shan AU - Dworkin, Lance PY - 2008/03/21/ UR - http://dx.doi.org/10.1074/jbc.M710396200 ER -