IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway

Chen, Nan; Debnath, Jayanta

doi:10.4161/auto.24870

Cited by 67 publications

(65 citation statements)

References 46 publications

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“…Such results are consistent with reports demonstrating that IKK, but not NFKB, is critical for basal and starvation-induced expression of autophagy genes [81]. Furthermore, a study in mammary epithelial cells demonstrates that the inhibition of IKK or known activators of IKK, such as MAP3K7, attenuates the autophagy response following loss of α3β1 integrin mediated ECM attachments [17]. Importantly, this study demonstrates that IKK mediated activation of detachment-induced autophagy occurs independently of both mTORC1 signaling and NFKB, once again corroborating that an alternative signaling mechanism underlies IKK-mediated regulation of autophagy following matrix detachment.…”

Section: Integrin Mediated Nfkb-ikk Signaling and Detachment-inducedsupporting

confidence: 91%

“…One such signaling pathway is autophagy, which was initially observed in electron microscopic studies of ECM-detached cells during lumen formation in glandular epithelial structures (acini) grown in three dimensional organotypic cultures [16]. Since those initial observations, studies have uncovered that the induction of autophagy is specifically due to the lack of integrin-mediated cell adhesion [3, 17]. At the molecular level, integrins translate extrinsic environmental changes to the intracellular environment and regulate the signals that promote autophagy induction [3, 18].…”

Section: Detachment-induced Autophagy and Anoikis Resistancementioning

confidence: 99%

“…Recent studies further defining the intracellular signals that regulate detachment-induced autophagy demonstrate a link between integrin function and the activation of the IκB kinase (IKK) complex [17]. IKK functions as a central regulator of the nuclear factor kappa B (NFKB) signaling pathway, which has been implicated in autophagy regulation as well as anoikis resistance [76, 77].…”

Section: Integrin Mediated Nfkb-ikk Signaling and Detachment-inducedmentioning

confidence: 99%

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The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

Vlahakis

Debnath

2017

Journal of Molecular Biology

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Autophagy is a cellular degradation process integral for promoting cellular adaptation during metabolic stress while also functioning as a cellular homeostatic mechanism. Mounting evidence also demonstrates that autophagy is induced upon loss of integrin-mediated cell attachments to the surrounding extracellular matrix (ECM). Analogous to its established cytoprotective role during nutrient starvation, autophagy protects cells from detachment-induced cell death, termed anoikis. Here, we review the significance of autophagy as an anoikis resistance pathway, focusing on the intracellular signals associated with integrins that modulate the autophagy response and dictate the balance between cell death and survival following loss of cell-matrix contact. In addition, we highlight recent studies demonstrating that autophagy functions in the upstream regulation of integrin-mediated cell adhesion via the control of focal adhesion remodeling, and discuss how these emerging interconnections between integrin-mediated adhesion pathways and autophagy influence cancer progression and metastasis.

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Section: Integrin Mediated Nfkb-ikk Signaling and Detachment-inducedsupporting

confidence: 91%

Section: Detachment-induced Autophagy and Anoikis Resistancementioning

confidence: 99%

Section: Integrin Mediated Nfkb-ikk Signaling and Detachment-inducedmentioning

confidence: 99%

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The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

Vlahakis

Debnath

2017

Journal of Molecular Biology

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“…Integrins (including α3) have been known to regulate autophagy in other systems (Chen and Debnath, 2013;Lock and Debnath, 2008), so we aimed to assess whether there were alterations in this process in integrin-α3 +/− mice. There was a higher proportion of presynaptic terminals that stained positive for the autophagic markers p62 (encoded by Sqstm1) and LC3 (encoded by Map1lc3) in mutant compared to WT mice ( Fig.…”

Section: Altered Nmj Maintenance and Autophagy At Integrin-α3-mutantmentioning

confidence: 99%

Multiple roles of integrin-α3 at the neuromuscular junction

Ross

Webster

Lechertier

et al. 2017

Journal of Cell Science

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The neuromuscular junction (NMJ) is the synapse between motoneurons and skeletal muscle, and is responsible for eliciting muscle contraction. Neurotransmission at synapses depends on the release of synaptic vesicles at sites called active zones (AZs). Various proteins of the extracellular matrix are crucial for NMJ development; however, little is known about the identity and functions of the receptors that mediate their effects. Using genetically modified mice, we find that integrin-α3 (encoded by Itga3), an adhesion receptor at the presynaptic membrane, is involved in the localisation of AZ components and efficient synaptic vesicle release. Integrin-α3 also regulates integrity of the synapse -mutant NMJs present with progressive structural changes and upregulated autophagy, features commonly observed during ageing and in models of neurodegeneration. Unexpectedly, we find instances of nerve terminal detachment from the muscle fibre; to our knowledge, this is the first report of a receptor that is required for the physical anchorage of pre-and postsynaptic elements at the NMJ. These results demonstrate multiple roles of integrin-α3 at the NMJ, and suggest that alterations in its function could underlie defects that occur in neurodegeneration or ageing.

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“…Integrins can activate various signaling pathways related to autophagy. The IκB kinase/nuclear factor-κB, mitogen-activated protein kinase and AMP-activated protein kinase pathways activate autophagy [16,17,18], while only the Akt pathway has inhibitory potential. β 3 -Integrin can also activate Akt signaling in macrophages when LPS is added and in isolated cardiomyocytes simulated by H 2 O 2 [19,20].…”

Section: Introductionmentioning

confidence: 99%

ß<sub>3</sub>-Integrin Inhibits Lipopolysaccharide-Induced Autophagy in Cardiomyocytes via the Akt Signaling Pathway

Zhu¹,

Li²,

Gong³

et al. 2015

Cardiology

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Objective: To investigate the role of β₃-integrin in lipopolysaccharide (LPS)-induced autophagy in cardiomyocytes and its underlying mechanism. Methods: β₃-Integrin expression in cardiomyocytes was up- or downregulated by adenovirus transfection or cyclic arginine-glycine-aspartic acid (cRGD) peptide treatment before LPS stimulation. The expression of autophagy-associated proteins (LC3-II, Beclin-1 and Bcl-2) and the activation of Akt were determined using Western blotting. Autophagosomes and autophagic vacuoles were observed using monodansylcadaverine (MDC) dye and transmission electron microscopy, respectively. Results: Downregulation of β₃-integrin with cRGD peptide resulted in enhanced LC3-II and Beclin-1 and decreased Bcl-2 expression. Low Beclin-1 levels were detected after LPS stimulation in adenovirus β₃-integrin-transfected cardiomyocytes. There was no significant difference in LC3-II levels between control and adenovirus β₃-integrin-transfected cardiomyocytes. Enhanced accumulation of MDC dye and autophagosomes, which were inhibited by β₃-integrin overexpression, were detected after LPS treatment. The increased phosphorylation of Akt after LPS stimulation was inhibited by cRGD and enhanced by β₃-integrin overexpression. Furthermore, the Akt inhibitor triciribine inhibited the negative effect of β₃-integrin on autophagy, as shown by LC3-II and Beclin-1 upregulation. Conclusions: β₃-Integrin inhibits LPS-induced autophagy in cardiomyocytes. The inhibition of Akt signaling might be an important mechanism in this process.

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IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway

Cited by 67 publications

References 46 publications

The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

Multiple roles of integrin-α3 at the neuromuscular junction

ß<sub>3</sub>-Integrin Inhibits Lipopolysaccharide-Induced Autophagy in Cardiomyocytes via the Akt Signaling Pathway

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