New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, 45122 Essen, Germany
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA
Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06520, USA
Author to whom correspondence should be addressed.
These authors contributed equal to this work.
Cancers 2018, 10(3), 78; https://doi.org/10.3390/cancers10030078
Received: 24 February 2018 / Revised: 15 March 2018 / Accepted: 16 March 2018 / Published: 18 March 2018
(This article belongs to the Special Issue Advances in the biological responses to radiation-induced DNA damage: A selection of papers from the Joint 43rd European Radiation Research Society (ERRS) and 20th German Society for Biological Radiation Research (GBS) Annual Meetings)
Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors. Here we review current knowledge on the mechanisms dictating Akt’s activation and target selection including the involvement of miRNAs and with focus on compartmentalization of the signaling network. Moreover, we discuss recent advances in the cross-talk with DNA damage response highlighting nuclear Akt target proteins with potential involvement in the regulation of DNA double strand break repair.