title: Platelet-derived growth factor-BB activates calcium/calmodulin-dependent and -independent mechanisms that mediate Akt phosphorylation in the neurofibromin-deficient human Schwann cell line ST88-14.
abstract: Neurofibromatosis type 1-derived Schwann cells isolated from malignant peripheral nerve sheath tumors (MPNSTs) overexpress PDGF receptor-β and generate an aberrant intracellular calcium increase in response to PDGF-BB. Using the human MPNST Schwann cell line ST88-14, we demonstrate that, in addition to a transient phosphorylation of Akt, PDGF-BB stimulation produces an atypical sustained phosphorylation of Akt that is dependent on calcium and calmodulin (CaM). The sustained Akt phosphorylation did not occur in PDGF-BB-stimulated normal human Schwann cells or ST88-14 cells stimulated with stem cell factor, whose receptor is also overexpressed in ST88-14 cells. The sustained Akt phosphorylation induced by PDGF-BB was inhibited by pretreatment of the cells with either the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester (BAPTA-AM) or the CaM antagonist W7, whereas the transient portion was not inhibited. Akt also co-immunoprecipitated with CaM in a PDGF-BB-dependent manner, suggesting that direct interaction between Akt and CaM is involved in the sustained phosphorylation of Akt. Furthermore, we provide evidence that anti-apoptotic effects of PDGF-BB on serum-deprived ST88-14 cells can be inhibited by W7, implicating the PDGF-BB-induced activation of calcium/CaM in promoting cell survival, presumably through sustained Akt activation. We conclude that the activation of the calcium/CaM/Akt pathway resulting from stimulation of overexpressed PDGF receptor-β may contribute to the survival and tumorigenicity of MPNST cells.
authors: Research Service, Edward Hines, Jr. Veterans Administration Hospital, Hines, Illinois 60141, USA. robert.farrer@va.gov
authors: Robert G
authors: RG
authors: Farrer
authors: Jason R
authors: JR
authors: Farrer
authors: George H
authors: GH
authors: DeVries
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000077214:Becaplermin; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009456:Neurofibromatosis 1 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D043925:Angiogenesis Inducing Agents; D002147:Calmodulin; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D025542:Neurofibromin 1; D020574:Proto-Oncogene Proteins c-sis; D013449:Sulfonamides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D000077214:Becaplermin; D004533:Egtazic Acid; C017967:W 7; D017479:Receptors, Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium