Cell adhesion suppresses autophagy via Src/FAK-mediated phosphorylation and inhibition of AMPK.
AMPK
Autophagy
Cell attachment
Src
Tyrosine phosphorylation
Journal
Cellular signalling
ISSN: 1873-3913
Titre abrégé: Cell Signal
Pays: England
ID NLM: 8904683
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
19
08
2021
revised:
10
10
2021
accepted:
11
10
2021
pubmed:
22
10
2021
medline:
1
4
2022
entrez:
21
10
2021
Statut:
ppublish
Résumé
Autophagy is a multi-step process regulated in part by AMP-activated protein kinase (AMPK). Phosphorylation of threonine 172 on the AMPK α-subunit enhances AMPK kinase activity, resulting in activation of downstream signaling. Integrin-mediated cell adhesion activates Src/ Focal Adhesion Kinase (FAK) signaling complex, which regulates multiple cellular processes including cell survival. We show here that Src signaling leads to direct phosphorylation of the AMPK-α subunit on a novel site, tyrosine 179, resulting in suppression of AMPK-T172 phosphorylation and autophagy upon integrin-mediated cell adhesion. By using chemical inhibitors, genetic cell models and targeted mutagenesis, we confirm an important role for Src and FAK in suppressing AMPK signaling and autophagy induced by various additional stimuli, including glucose starvation. Furthermore, we found that autophagy suppression by hydroxychloroquine promotes apoptosis in a cancer cell model that had been treated with Src inhibitors. Our findings reveal a link between the Src/ FAK complex and AMPK/ autophagy regulation, which may play an important role in the maintenance of normal cellular homeostasis and tumor progression.
Identifiants
pubmed: 34673141
pii: S0898-6568(21)00259-X
doi: 10.1016/j.cellsig.2021.110170
pmc: PMC8602780
mid: NIHMS1750724
pii:
doi:
Substances chimiques
Focal Adhesion Kinase 1
EC 2.7.10.2
Focal Adhesion Protein-Tyrosine Kinases
EC 2.7.10.2
src-Family Kinases
EC 2.7.10.2
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
110170Subventions
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
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