Inhibition of integrin-linked kinase/protein kinase B/Akt signaling: Mechanism for ganglioside-induced apoptosis

Xiao Qi Wang, Ping Sun, Amy S. Paller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Ganglioside GT1b inhibits keratinocyte attachment to and migration on a fibronectin matrix by binding to α5β1 and preventing α5β1 interaction with fibronectin. The role of gangliosides in triggering keratinocyte apoptosis, however, is unknown. Addition of GT1b to keratinocyte-derived SCC12 cells, grown in serum-free medium but exposed to fibronectin, suppressed Bad phosphorylation, activated caspase-9, and inhibited cyclin D and E expression, resulting in cell cycle arrest at G1 phase and initiation of apoptosis. The mechanism of GT1b activation of caspase-9 involved inhibition of β1 integrin serine/threonine phosphorylation and decreased phosphorylation of both integrin-linked kinase and protein kinase B/Akt at its Ser-473 site, leading to cytochrome c release from mitochondria. Consistently, blockade of GT1b function with anti-GT1b antibody specifically activated the Ser-473 site of Akt, markedly suppressing apoptosis. The ganglioside-induced inhibition of Akt phosphorylation was GT1b-specific and was not observed when cells were treated with other keratinocyte gangliosides, including GD3. These studies suggest that the modulation of keratinocyte cell cycle and survival by GT1b is mediated by its direct interaction with α5β1 and resultant inhibition of the integrin/integrin-linked kinase/protein kinase B/Akt signaling pathway.

Original languageEnglish (US)
Pages (from-to)44504-44511
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number48
DOIs
StatePublished - Nov 30 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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