Ganglioside loss promotes survival primarily by activating integrin-linked kinase/Akt without phosphoinositide 3-OH kinase signaling

Ping Sun, Xiao Qi Wang, Keith Lopatka, Suleman Bangash, Amy S. Paller

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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 β1 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.

Original languageEnglish (US)
Pages (from-to)107-117
Number of pages11
JournalJournal of Investigative Dermatology
Volume119
Issue number1
DOIs
StatePublished - Jul 2002

Keywords

  • Bad
  • Caspase-9
  • Cell cycle
  • Cyclin
  • Fibronectin

ASJC Scopus subject areas

  • Dermatology

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