G protein-coupled receptors and the regulation of autophagy

Wauson, Eric M.; Dbouk, Hashem A.; Ghosh, Anwesha; Cobb, Melanie H.

doi:10.1016/j.tem.2014.03.006

Cited by 67 publications

(65 citation statements)

References 103 publications

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“…Despite mounting evidence for a causal role of autophagy suppression in the promotion of compensatory hypertrophy (4,11,31,(42)(43)(44)(45)(46), the mechanistic links between pressure overload and adrenergic signaling-induced autophagic suppression have remained largely unsolved. A prior report indicated that endothelin-1 can suppress autophagy by inducing ubiquitination and degradation of Atg14L through ZBTB16-Cullin3-Rock1 E3 ubiquitin ligase complex (47).…”

Section: Discussionmentioning

confidence: 99%

Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth

Cheng

Zhu

Dee

et al. 2017

Journal of Biological Chemistry

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Autophagy is an evolutionarily conserved intracellular degradation/recycling system that is essential for cellular homeostasis but is dysregulated in a number of diseases, including myocardial hypertrophy. Although it is clear that limiting or accelerating autophagic flux can result in pathological cardiac remodeling, the physiological signaling pathways that fine-tune cardiac autophagy are poorly understood. Herein, we demonstrated that stimulation of cardiomyocytes with phenylephrine (PE), a well known hypertrophic agonist, suppresses autophagy and that activation of focal adhesion kinase (FAK) is necessary for PE-stimulated autophagy suppression and subsequent initiation of hypertrophic growth. Mechanistically, we showed that FAK phosphorylates Beclin1, a core autophagy protein, on Tyr-233 and that this post-translational modification limits Beclin1 association with Atg14L and reduces Beclin1-dependent autophagosome formation. Remarkably, although ectopic expression of wild-type Beclin1 promoted cardiomyocyte atrophy, expression of a Y233E phosphomimetic variant of Beclin1 failed to affect cardiomyocyte size. Moreover, genetic depletion of Beclin1 attenuated PE-mediated/FAK-dependent initiation of myocyte hypertrophy in vivo. Collectively, these findings identify FAK as a novel negative regulator of Beclin1-mediated autophagy and indicate that this pathway can facilitate the promotion of compensatory hypertrophic growth. This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux.Macroautophagy is an evolutionarily conserved intracellular degradation/recycling process in which cytoplasmic cargo is non-selectively enveloped within double-membraned vesicles called autophagosomes that are transported to and fuse with lysosomes. Within these so-called autolysosomes, cytoplasmic cargo and the inner membrane are degraded so that the amino acids, fatty acids, and glucose released can be used to support cellular metabolism or to synthesize new proteins. Cardiomyocytes are both highly metabolically active cells and long-lived cells and as such are particularly dependent on macroautophagy (hereafter referred to as autophagy) for energy production and removal of damaged organelles or misfolded proteins. However, in some cases up-regulation of autophagy (or failure of autophagy suppression) can lead to detrimental cardiac remodeling.Autophagy is regulated in a stepwise fashion that involves the formation of distinct protein complexes composed of autophagy-related genes (Atg proteins) and their enzymatic binding partners. Nutrient deprivation-induced activation of the AMP kinase/Unc-51-like autophagy-activating kinase 1 (ULK) kinase cascade leads to the recruitment of core proteins VPS34, VPS15, and Beclin1 (complex I) to endoplasmic reticulum exit sites to form phosphatidylinositol 1,4,5-phosphate 3-kinase-dependent double membrane autophagosome precursors. Complex I then facilitates the recruitment of additional proteins, includi...

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Section: Discussionmentioning

confidence: 99%

Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth

Cheng

Zhu

Dee

et al. 2017

Journal of Biological Chemistry

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“…These include (but are not limited to): (1) free fatty acid receptor 1 (FFAR1), FFAR2, FFAR3, and FFAR4, which are activated by free fatty acids; (2) glucagon receptor (GCGR), which responds to glucagon; (3) cholinergic receptor, muscarinic 3 (CHRM3), which is activated by acetylcholine; (4) adrenoceptor beta 2, surface (ADRB2), which is engaged by norepinephrine; and (5) purinergic receptor P2Y, G protein-coupled, 13 (P2RY13), which is responsive to ADP (Wauson et al, 2014). The signal transduction pathways that relay the liganddependent activation of these receptors to the autophagic machinery are heterogeneous but generally involve elevations in the intracellular levels of inositol-1,4,5,-triphosphate and diacylglycerol, or cAMP, which de facto stimulate autophagy via the AMPK/MTORC1 hub (Wauson et al, 2014).…”

Section: Initiation Of Autophagy By the Plasma Membranementioning

confidence: 99%

“…G protein-coupled receptor, class C, group 6, member A (GPRC6A), calcium-sensing receptor (CASR), gamma-aminobutyric acid B receptor 1 (GABBR1), heteromeric taste receptors, and various metabotropic glutamate receptors, all of which are activated by one or several amino acids, share the ability to repress autophagy in the presence of their ligands (Wauson et al, 2014). The molecular cascades connecting these GPCRs to the autophagic machinery are not completely understood but have been proposed to involve G proteins that provoke a decrease in the intracellular levels of cAMP, resulting in the suppression of AMPK activity (Wauson et al, 2014).…”

Section: ''Signal Off'' Pm-driven Autophagymentioning

confidence: 99%

“…The molecular cascades connecting these GPCRs to the autophagic machinery are not completely understood but have been proposed to involve G proteins that provoke a decrease in the intracellular levels of cAMP, resulting in the suppression of AMPK activity (Wauson et al, 2014). In addition, heteromeric taste receptors have been shown to repress autophagy via a Ca 2+ -dependent mechanism that directly involves amino acid sensing by MTORC1 (Wauson et al, 2012).…”

Section: ''Signal Off'' Pm-driven Autophagymentioning

confidence: 99%

“…Examples of Non-selective and Targeted Autophagic Responses Initiated at Specific Subcellular CompartmentsChen et al, 2014;Geisler et al, 2010;Okatsu et al, 2015;Narendra et al, 2010;Tanaka et al, 2010 CCFs destined to disposal have signs of ongoing DDR and are tagged with p62Ivanov et al, 2013;Young et al, 2009 Plasma membrane death receptor ligands non-selective stimulate autophagy via JNK1 and components of the NF-kB signaling pathwayCriollo et al, 2010; Criollo et al, 2011;He et al, 2012;Keller et al, 2011 promote autophagy via MYD88 or TICAM1Delgado et al, 2008;Knodler and Celli, 2011;Ma et al, 2013;Shi and Kehrl, 2008 amino acid deprivation non-selective several GPCRs repress autophagy in response to extracellular amino acidsWauson et al, 2012;Wauson et al, 2014Inoki et al, 2002Leto and Saltiel, 2012;Manning and Cantley, 2007;Wang et al, 2012; Wei et al, 2013 Continued …”

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confidence: 99%

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Organelle-Specific Initiation of Autophagy

et al. 2015

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Autophagy constitutes a prominent mechanism through which eukaryotic cells preserve homeostasis in baseline conditions and in response to perturbations of the intracellular or extracellular microenvironment. Autophagic responses can be relatively non-selective or target a specific subcellular compartment. At least in part, this depends on the balance between the availability of autophagic substrates ("offer") and the cellular need of autophagic products or functions for adaptation ("demand"). Irrespective of cargo specificity, adaptive autophagy relies on a panel of sensors that detect potentially dangerous cues and convert them into signals that are ultimately relayed to the autophagic machinery. Here, we summarize the molecular systems through which specific subcellular compartments-including the nucleus, mitochondria, plasma membrane, reticular apparatus, and cytosol-convert homeostatic perturbations into an increased offer of autophagic substrates or an accrued cellular demand for autophagic products or functions.

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G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

Arang

Gutkind

2020

FEBS Letters

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G protein‐coupled receptors (GPCRs) and heterotrimeric G proteins play central roles in a diverse array of cellular processes. As such, dysregulation of GPCRs and their coupled heterotrimeric G proteins can dramatically alter the signalling landscape and functional state of a cell. Consistent with their fundamental physiological functions, GPCRs and their effector heterotrimeric G proteins are implicated in some of the most prevalent human diseases, including a complex disease such as cancer that causes significant morbidity and mortality worldwide. GPCR/G protein‐mediated signalling impacts oncogenesis at multiple levels by regulating tumour angiogenesis, immune evasion, metastasis, and drug resistance. Here, we summarize the growing body of research on GPCRs and their effector heterotrimeric G proteins as drivers of cancer initiation and progression, and as emerging antitumoural therapeutic targets.

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G protein-coupled receptors and the regulation of autophagy

Cited by 67 publications

References 103 publications

Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth

Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth

Organelle-Specific Initiation of Autophagy

G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

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