Distinct biological roles for the akt family in mammary tumor progression.

The phosphatidylinositol 3' kinase/Akt pathway is frequently dysregulated in cancer, which can have unfavorable consequences in terms of cell proliferation, survival, metabolism, and migration. Increasing evidence suggests that Akt1, Akt2, and Akt3 play unique roles in breast cancer initiation and progression. We have recently shown that in contrast to Akt1, which accelerates mammary tumor induction in transgenic mice, Akt2 promotes metastasis of tumor cells without affecting the latency of tumor development. Despite the distinct phenotypic outputs resulting from Akt1 or Akt2 activation, very little is known about the mode by which such unique functions originate from these highly related kinases. Here we discuss potential mechanisms contributing to the differing functional specificity of Akt1 and Akt2 with respect to migration, invasion, and metastasis.

[1]  Kevin Struhl,et al.  MicroRNAs Differentially Regulated by Akt Isoforms Control EMT and Stem Cell Renewal in Cancer Cells , 2009, Science Signaling.

[2]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[3]  G. Mills,et al.  Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. , 2009, Cancer research.

[4]  T. McGraw,et al.  Insulin-modulated Akt subcellular localization determines Akt isoform-specific signaling , 2009, Proceedings of the National Academy of Sciences.

[5]  Takuya Kato,et al.  An actin-binding protein Girdin regulates the motility of breast cancer cells. , 2008, Cancer research.

[6]  A. Thorburn,et al.  Regulation of the Pro-apoptotic Scaffolding Protein POSH by Akt* , 2007, Journal of Biological Chemistry.

[7]  Jie Zhou,et al.  Akt1 governs breast cancer progression in vivo , 2007, Proceedings of the National Academy of Sciences.

[8]  A. Newton,et al.  PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. , 2007, Molecular cell.

[9]  W. Muller,et al.  The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer , 2007, Oncogene.

[10]  M. Birnbaum,et al.  Opposing Roles for Akt1 and Akt2 in Rac/Pak Signaling and Cell Migration* , 2006, Journal of Biological Chemistry.

[11]  J. Brugge,et al.  Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial–mesenchymal transition , 2005, The Journal of cell biology.

[12]  A. Toker,et al.  Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. , 2005, Molecular cell.

[13]  B. A. Ballif,et al.  Phosphorylation of ACAP1 by Akt regulates the stimulation-dependent recycling of integrin beta1 to control cell migration. , 2005, Developmental cell.

[14]  Robert D Cardiff,et al.  Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. , 2004, Cancer research.

[15]  B. Hemmings,et al.  Physiological functions of protein kinase B/Akt. , 2004, Biochemical Society transactions.

[16]  T. Dale,et al.  Protein Kinase B/Akt Acts via Glycogen Synthase Kinase 3 To Regulate Recycling of αvβ3 and α5β1 Integrins , 2004, Molecular and Cellular Biology.

[17]  C. Figueroa,et al.  Akt2 Negatively Regulates Assembly of the POSH-MLK-JNK Signaling Complex* , 2003, Journal of Biological Chemistry.

[18]  R. Cardiff,et al.  Activation of Akt (Protein Kinase B) in Mammary Epithelium Provides a Critical Cell Survival Signal Required for Tumor Progression , 2001, Molecular and Cellular Biology.

[19]  S. Naber,et al.  Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. , 2007, Cancer research.

[20]  B. Karlan,et al.  Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. , 2003, Cancer research.

[21]  Y. Pekarsky,et al.  Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.