Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTEN-knockout cells

Oncogene. 2004 Dec 16;23(58):9348-58. doi: 10.1038/sj.onc.1208147.

Abstract

Mutations in the tumor suppressor protein PTEN (phosphatase and tensin homologue deleted on chromosome 10) enhance cell migration, yet the underlying molecular mechanisms remain largely uncharacterized. Loss of PTEN in mouse embryonic fibroblasts (MEFs) correlates with striking cortical actin accumulation. However, how loss of PTEN leads to cortical actin formation and whether the presence of cortical actin contributes to the increased cell migration are unclear. Here we show that overexpression of dominant-negative forms of (DN) PTEN, RhoA or its kinase-dead (KD) effector, PKN, inhibited cortical actin formation, indicating that cortical actin of Pten(-/-) MEFs is mediated by the PTEN/Rho/PKN pathway. However, neither DN RhoA nor KD PKN inhibited the enhanced migration of Pten(-/-) cells, in contrast to the inhibitory effect of DN Rac. In agreement with the previous observation that DN Akt inhibits migration of Pten(-/-) cells, we demonstrate here that overexpression of KD PDK-1, the Akt kinase, reduces Pten(-/-) cell migration. Furthermore, overexpression of DN forms of Akt, Rac, or PDK-1, all of which inhibit migration of Pten(-/-) cells, had no effect on cortical actin accumulation. Our findings suggest that PDK-1/Akt signaling pathway plays a major role in regulating cell migration induced by PTEN deficiency.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Cell Line
  • Cell Movement / physiology*
  • Enzyme Activation
  • Mice
  • Mice, Knockout
  • PTEN Phosphohydrolase
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / physiology*
  • Protein-Serine-Threonine Kinases / physiology*
  • Protein-Tyrosine Kinases / physiology*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*

Substances

  • Tumor Suppressor Proteins
  • Protein-Tyrosine Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Protein Tyrosine Phosphatases
  • PTEN Phosphohydrolase
  • Pten protein, mouse