New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades

Pierce, Kristen L.; Luttrell, Louis M.; Lefkowitz, Robert J.

doi:10.1038/sj.onc.1204184

Cited by 378 publications

(289 citation statements)

References 53 publications

(55 reference statements)

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“…Arrestins, in addition to their "negative" role in G protein-mediated signaling, have "positive" signaling functions. Arrestins serve as a link between GPCRs and the mitogen-activated protein kinase (MAPK) signaling pathways (reviewed in [37,87]). Arrestins work as scaffolds recruiting a number of components of several MAPK cascades to activated GPCRs, thereby mediating activation of the MAPK pathways.…”

Section: Functional Significance Of Changes In Arrestin and Grk Exprementioning

confidence: 99%

“…Arrestins work as scaffolds recruiting a number of components of several MAPK cascades to activated GPCRs, thereby mediating activation of the MAPK pathways. In particular, both non-visual arrestins have been shown to activate ERK [66,87,100]. Over-expression of arrestins potentiates arrestin-mediated ERK activation [100,101].…”

Section: Functional Significance Of Changes In Arrestin and Grk Exprementioning

confidence: 99%

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Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Bychkov

Joyce

et al. 2008

Neurobiology of Aging

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Arrestins and G proteins-coupled receptor kinases (GRKs) regulate signaling and trafficking of G protein-coupled receptors. We investigated changes in the expression of arrestins and GRKs in the striatum of patients with Parkinson's disease without (PD) or with dementia (PDD) at post mortem using Western blotting and ribonuclease protection assay. Both PD and PDD groups had similar degree of dopamine depletion in all striatal regions. Arrestin proteins and mRNAs were increased in the PDD group throughout striatum. Protein and mRNA of GRK5, the major subtype in the human striatum, and GRK3 were also upregulated, whereas GRK2 and 6 were mostly unchanged. The PD group had lower concentration of arrestins and GRKs than the PDD group. There was no statistical link between the load of Alzheimer's pathology and the expression of these signaling proteins. Upregulation of arrestins and GRK in PDD may confer resistance to the therapeutic effects of levodopa often observed in these patients. In addition, increased arrestin and GRK concentrations may lead to dementia via perturbation of multiple signaling mechanisms.

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Section: Functional Significance Of Changes In Arrestin and Grk Exprementioning

confidence: 99%

Section: Functional Significance Of Changes In Arrestin and Grk Exprementioning

confidence: 99%

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Bychkov

Joyce

et al. 2008

Neurobiology of Aging

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“…First, this phenomenon is believed to be important for receptor resensitization (1) and receptor degradation (2). Second, it has been more recently appreciated that the internalization process is required for the activation of specific signaling cascades such as the activation of mitogenic signaling events (3). Numerous proteins are involved in the regulation of receptor endocytosis.…”

mentioning

confidence: 99%

G Protein-coupled Receptor Endocytosis in ADP-ribosylation Factor 6-depleted Cells

Houndolo

Boulay

Claing

2005

Journal of Biological Chemistry

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The internalization of G protein-coupled receptors is regulated by several important proteins that act in concert to finely control this complex cellular process. Here, we have applied the RNA interference approach to demonstrate that ADP-ribosylation factor 6 (ARF6) is essential for the endocytosis of a broad variety of receptors. Reduction of endogenous expression of ARF6 in HEK 293 cells resulted in a correlated inhibition of the ␤ 2 -adrenergic receptor internalization previously characterized as being sequestered via the clathrin-coated vesicle pathway. Furthermore, other receptors internalizing via this endocytic route, namely the angiotensin type 1 receptor and the vasopressin type 2 receptor, were also impaired in their ability to be sequestered when levels of endogenous ARF6 in cells were reduced. Interestingly, endocytosis of the endothelin type B receptor, characterized as being internalized via the caveolae pathway, was also markedly inhibited in ARF6-depleted cells. In contrast, internalization of the vasoactive intestinal peptide receptor was unaffected by reduced levels of ARF6. Finally, internalization of the acetylcholine-muscarinic type 2 receptor via the non-clathrincoated vesicle pathway was also inhibited in ARF6-depleted cells. Taken together, our results demonstrate that ARF6 proteins play an essential role in the internalization process of most G protein-coupled receptors regardless of the endocytic route being utilized. However, this phenomenon is not general. In some cases, another ARF isoform or other proteins may be essential to regulate the endocytic process.

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“…Therefore, in the G protein-dependent ERK activation by α 2A AR, arrestin serves as molecular switch, linking α 2A AR to the Src-dependent but not to the Src-independent pathway. The receptor tyrosine kinase, EGFR, is not required for α 2A ARevoked ERK signaling [71], despite their reported involvement in ERK activation by many other GPCRs [74].…”

Section: Arrestin Serves As a Molecular Switch Determining Src Involvmentioning

confidence: 98%

Regulation of α2AR trafficking and signaling by interacting proteins

Wang

Limbird

2007

Biochemical Pharmacology

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The continuing discovery of new G protein-coupled receptor (GPCR) interacting proteins and clarification of the functional consequences of these interactions has revealed multiple roles for these events. Some of these interactions serve to scaffold GPCRs to particular cellular micro-compartments or to tether them to defined signaling molecules, while other GPCR-protein interactions control GPCR trafficking and the kinetics of GPCR-mediated signaling transduction. This review provides a general overview of the variety of GPCR-protein interactions reported to date, and then focuses on one prototypical GPCR, the α 2 AR, and the in vitro and in vivo significance of its reciprocal interactions with arrestin and spinophilin.It seems appropriate to recognize the life and career of Arthur Hancock with a summary of studies that both affirm and surprise our preconceived notions of how nature is designed, as his career-long efforts similarly affirmed the complexity of human biology and attempted to surprise pathological changes in that biology with novel, discovery-based therapeutic interventions. Dr Hancock's love of life, of family, and of commitment to making the world a better place are a model of the life well lived, and truly missed by those who were privileged to know, and thus love, him.

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New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades

Cited by 378 publications

References 53 publications

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

G Protein-coupled Receptor Endocytosis in ADP-ribosylation Factor 6-depleted Cells

Regulation of α2AR trafficking and signaling by interacting proteins

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