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10.1074/jbc.M114.598649 http://scihub22266oqcxt.onion/10.1074/jbc.M114.598649 C4276863!4276863 !25384981     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25384981 &cmd=llinks): Failed to open stream: HTTP request failed! 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Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of ?F508-cystic fibrosis transmembrane conductance regulator (?F508-CFTR) |pdf=|usr=}}{{25384981 }} gab.com Text Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of F508-cystic fibrosis transmembrane conductance regulator ( F508-CFTR) JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=25384981 #FOAvip Cystic fibrosis (CF) is due to a folding defect in the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, ?F508, prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser(422). SGK1[Ser(P)(422)] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser(241). Then PDK1[Ser(P)(241)] phosphorylates SGK1[Ser(P)(422)] at Thr(256) to generate fully activated SGK1[Ser(422), Thr(P)(256)]. SGK1[Ser(P)(422),Thr(P)(256)] phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. ?F508-CFTR is thus free to traffic to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mammalian target of rapamycin signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of ?F508-CFTR (t½ ?10 h), enhances cAMP-activated chloride secretion, and suppresses hypersecretion of interleukin-8 (IL-8). We suggest that candidate drugs for CF directed against the PDK1/SGK1 signaling pathway, such as C4-CER, provide a novel therapeutic strategy for a life-limiting disorder that affects one child, on average, each day. Twit Text FOAVip Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of F508-cystic fibrosis transmembrane conductance regulator ( F508-CFTR) ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=25384981 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25384981 #FOAvip English Wikipedia <ref>{{Cite pmid|25384981 }}</ref> Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of ?F508-cystic fibrosis transmembrane conductance regulator (?F508-CFTR) #MMPMID25384981 Caohuy H ; Yang Q ; Eudy Y ; Ha TA ; Xu AE ; Glover M ; Frizzell RA ; Jozwik C ; Pollard HB J Biol Chem 2014[Dec]; 289 (52 ): 35953-68 PMID25384981 show ga Cystic fibrosis (CF) is due to a folding defect in the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, ?F508, prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser(422). SGK1[Ser(P)(422)] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser(241). Then PDK1[Ser(P)(241)] phosphorylates SGK1[Ser(P)(422)] at Thr(256) to generate fully activated SGK1[Ser(422), Thr(P)(256)]. SGK1[Ser(P)(422),Thr(P)(256)] phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. ?F508-CFTR is thus free to traffic to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mammalian target of rapamycin signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of ?F508-CFTR (t½ ?10 h), enhances cAMP-activated chloride secretion, and suppresses hypersecretion of interleukin-8 (IL-8). We suggest that candidate drugs for CF directed against the PDK1/SGK1 signaling pathway, such as C4-CER, provide a novel therapeutic strategy for a life-limiting disorder that affects one child, on average, each day. |Cell Line [MESH] |Cell Membrane/metabolism [MESH] |Ceramides/*pharmacology [MESH] |Cystic Fibrosis Transmembrane Conductance Regulator/genetics/*metabolism [MESH] |Cystic Fibrosis/drug therapy [MESH] |Drug Evaluation, Preclinical [MESH] |Endosomal Sorting Complexes Required for Transport/metabolism [MESH] |Enzyme Activation/drug effects [MESH] |Humans [MESH] |Immediate-Early Proteins/*metabolism [MESH] |Interleukin-8/metabolism [MESH] |Nedd4 Ubiquitin Protein Ligases [MESH] |Phosphatidylinositol 3-Kinases/metabolism [MESH] |Phosphorylation [MESH] |Protein Processing, Post-Translational [MESH] |Protein Serine-Threonine Kinases/*metabolism [MESH] |Protein Stability [MESH] |Protein Transport [MESH] |Pyruvate Dehydrogenase Acetyl-Transferring Kinase [MESH] |Sequence Deletion [MESH] |Signal Transduction [MESH] |Structure-Activity Relationship [MESH]Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- (epmc).pdf DeepDyve Pubget Overpricing