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Front Biol    2013, Vol. 8 Issue (4) : 421-433    https://doi.org/10.1007/s11515-013-1255-1
REVIEW
PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries
Chandler L. WALKER1,2,3,4, Nai-Kui LIU1,3,4, Xiao-Ming XU1,2,3,4()
1. Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; 2. Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; 3. Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; 4. Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Abstract

Brain and spinal cord injuries initiate widespread temporal and spatial neurodegeneration, through both necrotic and programmed cell death mechanisms. Inflammation, reactive oxidation, excitotoxicity and cell-specific dysregulation of metabolic processes are instigated by traumatic insult and are main contributors to this cumulative damage. Successful treatments rely on prevention or reduction of the magnitude of disruption, and interfering with injurious cellular responses through modulation of signaling cascades is an effective approach. Two intracellular signaling pathways, the phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling cascades play various cellular roles under normal and pathological conditions. Activation of both pathways can influence anatomical and functional outcomes in multiple CNS disorders. However, some mechanisms involve inhibiting or enhancing one pathway or the other, or both, in propagating specific downstream effects. Though many intracellular mechanisms contribute to cell responses to insult, this review examines the evidence exploring PTEN/PI3K and MAPK signaling influence on pathology, neuroprotection, and repair and how these pathways may be targeted for advancing knowledge and improving neurological outcome after injury to the brain and spinal cord.
Keywords spinal cord injury      traumatic brain injury      PTEN      MAPK      neuroprotection      axon regeneration     
Corresponding Author(s): XU Xiao-Ming,Email:xu26@iupui.edu   
Issue Date: 01 August 2013
 Cite this article:   
Chandler L. WALKER,Nai-Kui LIU,Xiao-Ming XU. PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries[J]. Front Biol, 2013, 8(4): 421-433.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-013-1255-1
https://academic.hep.com.cn/fib/EN/Y2013/V8/I4/421
Fig.1  PTEN reduces PI3K/Akt signaling benefits on cell survival and regeneration. PI3K can be stimulated through RTK or GPCR-mediated signaling, promoting Akt inhibition of several apoptosis-associated proteins such as Bad and FOXO1, and promotion of pro-survival mediators such as mTOR. PTEN antagonizes PI3K, and the resulting reduction in downstream Akt and mTOR signaling promotes programmed cell death i.e. apoptosis and autophagy. PI3K= Phosphatidylinositol 3-kinase; PTEN= Phosphatase and tensin homolog; mTOR= mammalian target of rapamycin; BAD= Bcl-2-associated death promoter; FOXO1= Forkhead box protein O1; LC3 II= Microtubule-associated protein light chain 3 II
Fig.2  MAPK signaling influences cell survival and injury. p38 and JNK MAPKs are most commonly associated with pathology following CNS injury. Erk signaling is most often viewed as a positive influence on cell fate, though it can contribute to cell death as well. JNK= Jun N-terminal kinase; MAPK= Mitogen activated protein kinase; Erk= Extracellular signal-regulated kinases.
Fig.3  Potential injury-mediated alterations of PI3K-Akt vs. MEK-Erk signaling. (A) Under normal conditions, these two pathways exhibit a steady-state balance of activity and inhibition. (B) After CNS injury however, Erk activity may increase while Akt signaling decreases, reducing its downstream inhibition of cell death progression, with p-Erk playing a role in these events.
PI3K pathway inhibitorTargetActionReference
Bisperoxovanadium (bpV)PTENInhibits PTEN phosphatase activity; Upregulates PI3K/Akt signalingSchmid et al., 2004
LY294002PI3 kinaseBlocks PI3K activity; Reduces phosphorylation of Akt at serine 473Vlahos et al., 1994
WortmanninPI3 kinaseBlocks PI3K activity; Reduces phosphorylation of Akt at serine 473Arcaro and Wymann, 1993
Akt inhibitor IVAktATP-competitive inhibitor of a kinase upstream of Akt but downstream of PI3KWang et al., 2006
RapamycinmTOR C1Inhibits mTOR’s ability to phosphorylate p70S6 kinase or 4E binding protein IKunz et al., 1993; Brown et al., 1994
MAPK pathway inhibitorsTargetActionReference
U0126MEK 1 and 2Blocks MEK phosphorylation and activation of Erk 1/2Favata et al., 1998
PD098059MEK 1 and 2Blocks MEK phosphorylation and activation of Erk 1/2Dudley et al., 1995
Tab.1  PI3K and MAPK pathway inhibitors, their targets and actions.
Fig.4  Overall PI3K and MAPK-Erk signaling is complex, but can highly influence the balance between cell survival and death. Multiple pathway inhibitors exist to further research cell signaling mechanisms. Though normal or pathological conditions can stimulate apoptotic cell death directly through death receptor and caspase activation, numerous signaling activities and interactions within a cell can indirectly influence cell fate. PI3K and MAPK pathways may individually, or through crosstalk, impact cell survival. For example, Akt may activate Erk to inhibit apoptosis. A variety of compounds targeting proteins within these cascades can help deepen our understanding of the complexities of PI3K and MAPK signaling in CNS pathology and protection. FasL= Fas ligand; TNFα = Tumor necrosis factor alpha; MAPKK kinase= Mitogen activated protein kinase kinase kinase; MEK= Mitogen activated protein kinase kinase; Erk= Extracellular signal-regulated kinases; PI3K= Phosphatidylinositol 3-kinase; PTEN= Phosphatase and tensin homolog; mTOR= mammalian target of rapamycin; BAD= Bcl-2-associated death promoter.
Fig.5  Neuroprotective and functional benefits of bpV(pic) treatment following SCI. (A) bpV(pic) reduced overall lesion volume following contusive cervical SCI. Cavitation common to both rat and human SCI is also reduced following bpV treatment in rats. Scale bar= 1 mm. (B) Sensorimotor functional outcome is also improved by bpV(pic) therapy, as determined by a treateating assessment. (C) Reduction of LC3-positive punctate autophagosomes are reduced in motor neurons following bpV(pic) treatment. Scale bar= 50 Ym. (D) Western blot analysis suggests bpV(pic) promotes Akt activity through inhibition of PTEN activity rather than expression. Also, reduction of autophagosome formation through diminished LC3 II/LC3I protein ratio after bpV treatment correlates with functional recovery and anatomical preservation, suggesting a potential mechanism of bpV-mediated neuroprotection. bpV(pic) = Dipotassium bisperoxo (picolinato) oxovanadate; LC3 II/I= microtubule associated protein light chain 3 II/I. LC3 I is the cytoplasmic form, while LC3 II is the lipidated form and classic autophagosome marker. * = <0.05; ** = <0.01 compared with Vehicle. [Modified from Walker et al. () ].
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