The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
A Non-canonical MEK/ERK Signaling Pathway Regulates Autophagy via Regulating Beclin 1
Open accessAbstract
Autophagy-essential proteins are the molecular basis of protective or destructive autophagy machinery. However, little is known about the signaling mechanisms governing these proteins and the opposing consequences of autophagy in mammals. Here we report that a non-canonical MEK/ERK module, which is positioned downstream of AMP-activated protein kinase (AMPK) and upstream of tuberous sclerosis complex (TSC), regulates autophagy by regulating Beclin 1. Depletion of ERK partially inhibited autophagy, whereas specific inhibition on MEK completely inhibited autophagy. MEK could bypass ERK to promote autophagy. Basal MEK/ERK activity conferred basal Beclin 1 by preventing disassembly of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. Activation of MEK/ERK by AMPK upon autophagy stimuli disassembled mTORC1 via binding to and activating TSC but disassembled mTORC2 independently of TSC. Inhibition of mTORC1 or mTORC2 by transiently or moderately activated MEK/ERK caused moderately enhanced Beclin 1 resulting in cytoprotective autophagy, whereas inhibition of both mTORC1 and mTORC2 by sustained MEK/ERK activation caused strongly pronounced Beclin 1 leading to cytodestructive autophagy. Our findings thus propose that the AMPK-MEK/ERK-TSC-mTOR pathway regulation of Beclin 1 represents different thresholds responsible for a protective or destructive autophagy.
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Cites
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Metadata
- Authors
- Wang, J., Whiteman, M. W., Lian, H., Wang, G., Singh, A., Huang, D., & Denmark, T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 284
- Issue
- 32
- Pages
- 21412-21424
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2019576484
- Cited by
- 319
- References
- 13
- FWCI
- 10.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
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