Over-expression of the p110β but not p110α isoform of PI 3-kinase inhibits motility in breast cancer cells

Shu Chin Yip, Mirvat El-Sibai, Karen M. Hill, Haiyan Wu, Zheng Fu, John S. Condeelis, Jonathan M. Backer

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Phosphoinositide 3-kinase (PI 3-kinase) activity is required for growth factor-induced cytoskeletal regulation and cell migration. We previously found that in MTLn3 rat adenocarcinoma cells, EGF-stimulated induction of actin barbed ends and lamellipod extension specifically requires the p85/p110α isoform of PI 3-kinase. To further characterize signaling by distinct PI 3-kinase isoforms, we have developed MTLn3 cells that transiently or stably overexpress either p110α or p110β. Transient overexpression of p110β inhibited EGF-stimulated lamellipod extension, whereas p110α-transfected cells showed normal EGF-stimulated lamellipod extension. Similar results were obtained by overexpression of kinase-dead p110β, suggesting that effects on cytoskeletal signaling were due to competition with p85/p110α complexes. Stable overexpression of p110α appeared to be toxic, based on the difficulty in obtaining stable overexpressing clones. In contrast, cells expressing a 2-fold increase in p110β were readily obtainable. Interestingly, cells stably expressing p110 β showed a marked inhibition of EGF-stimulated lamellipod extension. Using computer-assisted analysis of time-lapse images, we found that overexpression of p110β caused a nearly complete inhibition of motility. Cells overexpressing p110 β showed normal activation of Akt and Erk, suggesting that overall PI 3-kinase signaling was intact. A chimeric p110 molecule containing the p85-binding and Ras-binding domains of p110α and the C2, helical, and kinase domains of p110β, was catalytically active yet also inhibited EGF-stimulated lamellipod extension. These data highlight the differential signaling by distinct p110 isoforms. Identification of effectors that are differently regulated by p110α versus p110β will be important for understanding cell migration and its role in metastasis.

Original languageEnglish (US)
Pages (from-to)180-188
Number of pages9
JournalCell Motility and the Cytoskeleton
Volume59
Issue number3
DOIs
StatePublished - Nov 1 2004

Keywords

  • Actin
  • Adenocarcinoma
  • Breast cancer
  • Motility
  • PI 3-kinase

ASJC Scopus subject areas

  • Structural Biology
  • Cell Biology

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