title: CH-ILKBP regulates cell survival by facilitating the membrane translocation of protein kinase B/Akt.
abstract: Cell survival depends on proper propagation of protective signals through intracellular signaling intermediates. We report here that calponin homology domain-containing integrin-linked kinase (ILK)-binding protein (CH-ILKBP), a widely expressed adaptor protein localized at plasma membrane-actin junctions, is essential for transmission of survival signals. Cells that are depleted of CH-ILKBP undergo extensive apoptosis despite the presence of cell-extracellular matrix contacts and soluble growth factors. The activating phosphorylation of protein kinase B (PKB/Akt), a key regulator of apoptosis, is impaired in the absence of CH-ILKBP. Importantly, loss of CH-ILKBP prevents the membrane translocation of PKB/Akt. Furthermore, forced membrane targeting of PKB/Akt bypasses the requirement of CH-ILKBP for the activating phosphorylation of PKB/Akt, suggesting that CH-ILKBP is required for the membrane translocation but not the subsequent phosphorylation of PKB/Akt. Finally, we show that loss of CH-ILKBP is also required for the full activation of extracellular signal-regulated kinase (ERK)1/2. However, restoration of the PKB/Akt activation is sufficient for protection of cells from apoptosis induced by the depletion of CH-ILKBP despite the persistent suppression of the ERK1/2 activation. Thus, CH-ILKBP is an important component of the prosurvival signaling pathway functioning primarily by facilitating the membrane translocation of PKB/Akt and consequently the activation of PKB/Akt in response to extracellular survival signals.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Fukuda
authors.forename: Lida
authors.initials: L
authors.lastname: Guo
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Shi
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
mesh_terms: D000185:Actinin; D017209:Apoptosis; D001692:Biological Transport; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002470:Cell Survival; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008840:Microfilament Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000099200:Scaffold Protein ILK; D000096985:Calponins
chemical_list: D000185:Actinin; D002352:Carrier Proteins; D020169:Caspases; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D008840:Microfilament Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D000099200:Scaffold Protein ILK; C486590:PARVA protein, human; D000096985:Calponins; C486591:PARVB protein, human; C494918:AKT1 protein, human