PI 3 K-Akt regulation as a molecular mechanism of the stress response during aerobic dormancy

The biochemical mechanisms that direct intracellular signal transduction networks have been extensively studied in a variety of organisms spanning invertebrates to vertebrates. Depending on environmental conditions, animals may adjust these cellular pathways in favour of growth signals or, at the opposite extreme, initiate death signals. Animals living in extreme environments are often faced with stresses (e.g. oxygen, water and/or fuel limitation, temperature extremes) and as a result have evolved adaptations that ensure safe transitions into hypometabolic states (e.g. dormancy, hibernation, aestivation, diapauses, etc.) when conditions are unfavourable for normal life. Metabolic rate may be reduced by as much as 70-99% as compared with active states and a variety of preservation strategies may be activated, all relying on the restructuring of evolutionarily conserved metabolic pathways. Akt/PKB is a pivotal stress kinase which exerts control over pathways including glucose metabolism Correspondence/Reprint request: Dr. Kenneth B. Storey, Institute of Biochemistry & Department of Biology Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada E-mail: kenneth_storey@carleton.ca Jing Zhang et al. 148 (through GSK-3), protein synthesis (through mTOR), cell cycle regulation (through p27 and MDM2), and apoptosis (through BAD and caspases). In addition, via cross-talk with the NF-κB, Wnt, and MAPK signalling pathways, Akt/PKB is placed in a unique regulatory position in the stress response. By evaluating the natural responses of Akt/PKB signalling in diverse animal groups facing a range of stress challenges, researchers will discover the cellular plasticity of central metabolic pathways, how these pathways may be altered depending on the needs of the organism, and finally unravel important regulatory secrets involved in hundreds of stress and disease pathologies. List of symbols and abbreviations 4EBP eIF4E binding protein Apaf-1 apoptotic protease activating factor 1 ASK1 apoptotic signal-regulated kinase 1 (also called MAPKKK5) BAD Bcl-2-associated death promoter Bcl-2 B-cell lymphoma 2 Bcl-XL B-cell lymphoma-extra large c-Jun cellular-jun c-Myc cellular-myc CDK cyclin dependent kinase CDKI cyclin-dependent kinase inhibitor Chk1 checkpoint kinase 1 Cip CDK-interacting protein CK2 casein kinase 2 CREB cAMP response element-binding eEF eukaryotic elongation factor eIF eukaryotic initiation factor ERK extracellular signal-regulated protein kinase FOXO forkhead box O FRP frizzled related protein GβL G-protein β-subunit like protein (also called LST8) GLUT glucose transporter GSK-3 glycogen synthase kinase 3 HIF-1α hypoxia inducible factor 1, α subunit HM hydrophobic motif domain HSF-1 heat shock factor-1 HSP heat shock protein I-R ischemia-reperfusion Akt and regulation of aerobic dormancy 149 IGF-1 insulin-like growth factor-1 IGF-1R IGF-1 receptor IKK IκB kinase IL-1 interleukin-1 INK4 inhibitor of CDK4 IRS insulin receptor substrate JNK c-Jun N-terminal kinase Kip kinase inhibition protein MAPK mitogen-activated protein kinase MAPKK MAPK kinase MAPKKK MAPK kinase kinase, also known as MEKK MCL-1 myeloid cell leukemia sequence 1 MDM2 murine double minute 2 MK2 MAPK-activated protein kinase-2 MPF M-phase promoting factor mTOR mammalian target of rapamycin mTORC1 mTOR complex 1 NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells NFAT nuclear factor of activated T-cells Nrf2 NFE2L2, or nuclear factor (erythroid-derived 2)like 2) p70-S6K ribosomal protein S6 kinase, 70 kDa PDGF platelet-derived growth factor PDK1 phosphoinositide-dependent kinase-1 PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha PH pleckstrin homology domain PI3K Phosphoinositide 3-kinase PIF PDK1-interacting fragment PIP phosphatidylinositol phosphate PKB protein kinase B PRAS40 Proline-rich Akt Substrate 40 kDa PTEN phosphatase and tensin homologue RAC-PK related to the A and C protein kinase Raptor regulatory associated protein of mTOR Rictor rapamycin-insensitive companion of mTOR ROS reactive oxygen species SAPK stress-activated protein kinase SGK Serum/glucocorticoid regulated kinase S6K ribosomal protein S6 kinase Jing Zhang et al. 150 SHIP SH2 domain-containing inositol 5′-phosphatase TNF tumor necrosis factor TSC tuberous sclerosis Wnt wingless int