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Critical role for lipid raft-associated Src kinases in activation of PI3K-Akt signalling

Alexandre Arcaro1, Muriel Aubert, Maria E Espinosa del Hierro

  • 1Lung Cancer Biology Group, Division of Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, United Kingdom. Alexandre.Arcaro@kispi.unizh.ch

Cellular Signalling
|February 6, 2007
PubMed

Insights

Lipid rafts are crucial for growth factor signaling in small cell lung cancer (SCLC). They facilitate the activation of phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB)/Akt, driving SCLC cell growth.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Lipid rafts are membrane microdomains with unclear roles in growth factor signaling.
  • Small cell lung cancer (SCLC) cells utilize specific growth factor receptors like c-Kit.

Purpose of the Study:

  • To investigate the role of lipid rafts in growth factor signaling pathways in SCLC.
  • To determine the involvement of lipid rafts in the activation of phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB)/Akt.

Main Methods:

  • Studied association of growth factor receptors (c-Kit) with lipid rafts in SCLC cells.
  • Investigated the activation of PI3K and PKB/Akt in response to stem cell factor (SCF) under conditions of lipid raft disruption.
  • Utilized fibroblasts with targeted deletion of Src family kinase genes.
  • Examined the effect of Src kinase inhibition and a constitutively active Src mutant on signaling pathways.

Main Results:

  • Specific growth factor receptors, including c-Kit, associate with lipid rafts in SCLC cells.
  • Lipid raft integrity is essential for Src activation by stem cell factor (SCF).
  • Disruption of lipid rafts selectively inhibited PKB/Akt activation by SCF.
  • Inhibition of Src kinases blocked PKB/Akt activation and SCLC cell proliferation.
  • Src kinases are confirmed to mediate PKB/Akt activation by growth factor receptors.
  • Constitutively active Src stimulated PI3K/Akt signaling within lipid rafts, suggesting a role in oncogenic signaling.

Conclusions:

  • Lipid rafts play a critical role in activating phosphoinositide 3-kinase (PI3K) signaling by facilitating the interaction between Src kinases and PI3K isoforms.
  • These microdomains are important for oncogenic signaling pathways in cancer cells.
  • Targeting lipid rafts or associated kinases could be a therapeutic strategy for SCLC.

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