mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system
Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that invol...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/14908 |
| _version_ | 1811253418879090688 |
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| author | Linqing Miao Liu Yang Haoliang Huang Feisi Liang Chen Ling Yang Hu |
| author_facet | Linqing Miao Liu Yang Haoliang Huang Feisi Liang Chen Ling Yang Hu |
| author_sort | Linqing Miao |
| collection | DOAJ |
| description | Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration. |
| first_indexed | 2024-04-12T16:49:45Z |
| format | Article |
| id | doaj.art-41f85a7f6f8a4c929b31cb165b2faf72 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:49:45Z |
| publishDate | 2016-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-41f85a7f6f8a4c929b31cb165b2faf722022-12-22T03:24:25ZengeLife Sciences Publications LtdeLife2050-084X2016-03-01510.7554/eLife.14908mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous systemLinqing Miao0Liu Yang1Haoliang Huang2Feisi Liang3Chen Ling4Yang Hu5https://orcid.org/0000-0002-7980-1649Shriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United StatesShriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United StatesShriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United StatesShriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United StatesDivision of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, United StatesShriners Hospitals Pediatric Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, United States; Department of Anatomy and Cell Biology, Temple University Lewis Katz School of Medicine, Philadelphia, United StatesInjured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.https://elifesciences.org/articles/14908axon regenerationAKTmTORC1mTORC2GSK3optic nerve |
| spellingShingle | Linqing Miao Liu Yang Haoliang Huang Feisi Liang Chen Ling Yang Hu mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system eLife axon regeneration AKT mTORC1 mTORC2 GSK3 optic nerve |
| title | mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system |
| title_full | mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system |
| title_fullStr | mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system |
| title_full_unstemmed | mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system |
| title_short | mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system |
| title_sort | mtorc1 is necessary but mtorc2 and gsk3β are inhibitory for akt3 induced axon regeneration in the central nervous system |
| topic | axon regeneration AKT mTORC1 mTORC2 GSK3 optic nerve |
| url | https://elifesciences.org/articles/14908 |
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