title: Ganglioside loss promotes survival primarily by activating integrin-linked kinase/Akt without phosphoinositide 3-OH kinase signaling.
abstract: Keratinocyte gangliosides influence cellular functions, including proliferation, adhesion, migration, and differentiation. The effects of endogenous depletion of membrane gangliosides by gene transfection of a human ganglioside-specific sialidase on cell survival were investigated. Ganglioside depletion promotes survival of the human keratinocyte-derived SCC12 cell line through upregulated phosphorylation of beta1 integrin, and increased phosphorylation and activity of integrin-linked kinase, protein kinase B/Akt, and Bad, with resultant inhibition of caspase-9 activation. Ganglioside deficiency also increases expression of cyclins D1 and E, promoting cell cycle progression from G1 phase to S phase. Inhibition of either protein kinase B/Akt or integrin-linked kinase activity renders the ganglioside-deficient cells susceptible to triggers of apoptosis. Both serine-473 and threonine-308 sites of protein kinase B/Akt show increased phosphorylation in ganglioside-deficient cells, but the cell survival correlates with increased phosphorylation of the serine-473 site of Akt, not with increased phosphorylation of the threonine-308 site. Consistently, blockade of ganglioside GT1b function activates integrin-linked kinase and only the serine-473 site of protein kinase B/Akt. In contrast, antibody-induced blockade of GM3 function increases only threonine-308 phosphorylation of ganglioside-deficient cells. Whereas blockade of phosphoinositide 3-OH kinase function suppresses threonine-308 phosphorylation, it neither inhibits serine-473 phosphorylation nor triggers apoptosis. These data suggest that ganglioside depletion modulates cell survival primarily through protein kinase B/Akt stimulation by a pathway that does not require phosphoinositide 3-OH kinase and epidermal growth factor receptor signaling.
authors.affiliation: Department of Pediatrics, Children's Memorial Institute for Education and Research, North-western University Medical School, 2300 Children's Plaza, Chicago, IL 60614, U.S.A.
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Wang
authors.forename: Keith
authors.initials: K
authors.lastname: Lopatka
authors.forename: Suleman
authors.initials: S
authors.lastname: Bangash
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002294:Carcinoma, Squamous Cell; D002352:Carrier Proteins / Q000378:metabolism; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D018076:DNA, Complementary; D005353:Fibronectins / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology*; D009439:Neuraminidase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016196:S Phase / Q000502:physiology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms; D013912:Threonine / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D051025:bcl-Associated Death Protein; D000099200:Scaffold Protein ILK
chemical_list: D002352:Carrier Proteins; D053453:Caspase 9; D020169:Caspases; D019938:Cyclin D1; D019927:Cyclin E; D018076:DNA, Complementary; D005353:Fibronectins; D005732:Gangliosides; D019012:Integrin beta1; D009439:Neuraminidase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D013912:Threonine; D051025:bcl-Associated Death Protein; D000099200:Scaffold Protein ILK; C494819:BAD protein, human; C494918:AKT1 protein, human; C506433:CASP9 protein, human