The Endosomal Sorting Complex Required for Transport Pathway Mediates Chemokine Receptor CXCR4-promoted Lysosomal Degradation of the Mammalian Target of Rapamycin Antagonist DEPTOR

Verma, Rita; Marchese, Adriano

doi:10.1074/jbc.m114.606699

Cited by 24 publications

(26 citation statements)

References 84 publications

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“…For DNA transfections, HeLa cells grown on 6-cm cell culture dishes were transiently transfected with 3 g of empty vector (pCMV-10), FLAG-␤-arrestin1(25-161), FLAG-STAM1(296 -380), empty shRNA vector (pLKO), or shSTAM1 using polyethylenimine (PEI; catalog number 23966, Polysciences, Warrington, PA) similarly to what we have described previously (29). For siRNA transfections, HeLa cells were grown on 6-cm cell culture dishes and transfected with siRNA (50 nM final concentration) against luciferase, ␤-arrestin1, or FAK using Lipofectamine 3000 transfection reagent (Invitrogen) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…STAM1 is also involved in CXCR4-promoted Akt signaling, but this also likely does not involve the pool that is involved in ERK-1/2 signaling (Fig. 3B), although we have yet to investigate whether ␤-arrestin1 has a role (29). It is still possible that the minigenes may impact ERK-1/2 or Akt signaling via other GPCRs as ␤-arrestins scaffold several proteins involved in these pathways (40,41).…”

Section: ␤-Arrestin1⅐stam1mentioning

confidence: 99%

“…We next explored whether expression of ␤Arr1(25-161) or STAM1(296 -380) has an impact on G protein coupling by examining ERK-1/2 and Akt signaling, which are activated via G protein-dependent pathways by CXCR4 in HeLa cells (28,29) and are also required for CXCR4-promoted chemotaxis (30,31). Expression of ␤Arr1(25-161) or STAM1(296 -380) did not impact CXCL12-promoted activation of Akt (Fig.…”

Section: Disruption Of the ␤-Arrestin1⅐stam1mentioning

confidence: 99%

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β-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4

Alekhina

Marchese

2016

Journal of Biological Chemistry

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Edited by Henrik DohlmanThe chemokine receptor CXCR4 and its chemokine ligand CXCL12 mediate directed cell migration during organogenesis, immune responses, and metastatic disease. However, the mechanisms governing CXCL12/CXCR4-dependent chemotaxis remain poorly understood. Here, we show that the ␤-arrestin1⅐ signal-transducing adaptor molecule 1 (STAM1) complex, initially identified to govern lysosomal trafficking of CXCR4, also mediates CXCR4-dependent chemotaxis. Expression of minigene fragments from ␤-arrestin1 or STAM1, known to disrupt the ␤-arrestin1⅐STAM1 complex, and RNAi against ␤-arrestin1 or STAM1, attenuates CXCL12-induced chemotaxis. The ␤-arrestin1⅐STAM1 complex is necessary for promoting autophosphorylation of focal adhesion kinase (FAK). FAK is necessary for CXCL12-induced chemotaxis and associates with and localizes with ␤-arrestin1 and STAM1 in a CXCL12-dependent manner. Our data reveal previously unknown roles in CXCR4-dependent chemotaxis for ␤-arrestin1 and STAM1, which we propose act in concert to regulate FAK signaling. The ␤-arrestin1⅐STAM1 complex is a promising target for blocking CXCR4-promoted FAK autophosphorylation and chemotaxis.Chemotaxis is a process by which cells move toward or away from a chemical signal in a directed manner (1). The chemokine receptor CXCR4 and its ligand CXCL12 mediate chemotaxis of many cell types, and in this way this ligand/receptor pair is important during organ development, immune responses, and stem cell mobilization among other processes (2-5). CXCL12/ CXCR4-mediated chemotaxis is also involved in several pathologies, in particular cancer (6, 7). CXCR4 is up-regulated in several solid and hematological tumors and together with CXCL12 plays an important role in metastatic disease (8). Metastases are formed by several sequential steps that enable cancer cells from the primary tumor to disseminate to new organ sites through the vascular system (9). This has been linked in part to migration of CXCR4-expressing cancer cells to organs that express CXCL12 (6, 10). Despite the role of CXCR4-dependent cell migration in health and disease, the mechanisms remain poorly understood.CXCR4 belongs to the G protein-coupled receptor (GPCR) 2 family, and typically CXCR4-dependent chemotaxis occurs via G protein-dependent signaling pathways (11). However, ␤-arrestin-dependent signaling also contributes to CXCR4-dependent chemotaxis (12). CXCL12-promoted migration of T cells and B cells isolated from the spleen of ␤-arrestin2 knockout mice is attenuated compared with cells isolated from matched wild-type mice (12). In HEK293 cells, ␤-arrestin-promoted migration induced by CXCL12 occurs via a p38-dependent pathway (13). ␤-Arrestins interact with several proteins that regulate the actin cytoskeleton, which undergoes reorganization in response to chemotactic signals acting on other GPCRs (14 -16). These studies highlight the fact that ␤-arrestins regulate cell migration via multiple mechanisms, but detailed insight is lacking. ␤-Arrestins also negatively regulate CXCR4 sig...

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Section: Methodsmentioning

confidence: 99%

Section: ␤-Arrestin1⅐stam1mentioning

confidence: 99%

Section: Disruption Of the ␤-Arrestin1⅐stam1mentioning

confidence: 99%

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β-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4

Alekhina

Marchese

2016

Journal of Biological Chemistry

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“…During embryogenesis, the neurons of the vertebrate sympathetic and sensory ganglia are dependent on the neurotrophic factors derived from their targets for survival and maintenance of differentiated functions and this depends significantly on the Akt signaling pathway . Activation of the chemokine receptor, CXCR4, promotes degradation of DEPTOR (DEP domain‐containing mTOR‐interacting protein), one of the subunits of mTORC2, which in turn attenuates Akt signaling . Loss of ESCRT‐I and ‐III leads to elevated levels of DEPTOR and abrogates Akt signaling .…”

Section: Linking Escrt Pathway To Cell Death During Neurodegenerationmentioning

confidence: 99%

“…93,94 Activation of the chemokine receptor, CXCR4, promotes degradation of DEPTOR (DEP domain-containing mTOR-interacting protein), one of the subunits of mTORC2, which in turn attenuates Akt signaling. 95 Loss of ESCRT-I and -III leads to elevated levels of DEPTOR and abrogates Akt signaling. 95 Also reported is that a highly potent Akt inhibitor efficiently induces autophagy via an mTOR-independent pathway in cultured primary neuronal cells.…”

Section: Regulating Cell Survival Via Akt Signalingmentioning

confidence: 99%

Endosomal sorting complexes required for ESCRTing cells toward death during neurogenesis, neurodevelopment and neurodegeneration

Kaul

Chakrabarti

2018

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The endosomal sorting complexes required for transport (ESCRT) proteins help in the recognition, sorting and degradation of ubiquitinated cargoes from the cell surface, long-lived proteins or aggregates, and aged organelles present in the cytosol. These proteins take part in the endo-lysosomal system of degradation. The ESCRT proteins also play an integral role in cytokinesis, viral budding and mRNA transport. Many neurodegenerative diseases are caused by toxic accumulation of cargo in the cell, which causes stress and ultimately leads to neuronal death. This accumulation of cargo occurs because of defects in the endo-lysosomal degradative pathway-loss of function of ESCRTs has been implicated in this mechanism. ESCRTs also take part in many survival processes, lack of which can culminate in neuronal cell death. While the role played by the ESCRT proteins in maintaining healthy neurons is known, their role in neurodegenerative diseases is still poorly understood. In this review, we highlight the importance of ESCRTs in maintaining healthy neurons and then suggest how perturbations in many of the survival mechanisms governed by these proteins could eventually lead to cell death; quite often these correlations are not so obviously laid out. Extensive neuronal death eventually culminates in neurodegeneration.

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Glucagon's Metabolic Action in Health and Disease

Zeigerer

Sekar

Kleinert

et al. 2021

Comprehensive Physiology

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Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for its ability to directly act on the liver to increase de novo glucose production and to inhibit glycogen breakdown, glucagon lowers body weight by decreasing food intake and by increasing metabolic rate. Glucagon further promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects in the heart. Interestingly, recent decades have witnessed a remarkable renaissance of glucagon's biology with the acknowledgment that glucagon has pharmacological value beyond its classical use as rescue medication to treat severe hypoglycemia. In this article, we summarize the multifaceted nature of glucagon with a special focus on its hepatic action and discuss the pharmacological potential of either agonizing or antagonizing the glucagon receptor for health and disease.

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The Endosomal Sorting Complex Required for Transport Pathway Mediates Chemokine Receptor CXCR4-promoted Lysosomal Degradation of the Mammalian Target of Rapamycin Antagonist DEPTOR

Cited by 24 publications

References 84 publications

β-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4

β-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4

Endosomal sorting complexes required for ESCRTing cells toward death during neurogenesis, neurodevelopment and neurodegeneration

Glucagon's Metabolic Action in Health and Disease

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