Agonist-dependent Recruitment of Phosphoinositide 3-Kinase to the Membrane by β-Adrenergic Receptor Kinase 1

Prasad, Sathyamangla V. Naga; Barak, Larry S.; Rapacciuolo, Antonio; Caron, Marc G.; Rockman, Howard A.

doi:10.1074/jbc.m102376200

Cited by 171 publications

(180 citation statements)

References 35 publications

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“…The discrepancy is most likely due to the different β 2 AR expression methods used. Our study was performed in stably transfected HEK293 cells, which have a much higher initial rate of β 2 AR endocytosis and higher coupling efficiencies than the transiently transfected HEK293 cell systems utilized in the other studies [43]. Furthermore, we observed the same results on endocytosis using an independently derived stably transfected line of HEK293 cells (data not shown).…”

Section: Discussionsupporting

confidence: 64%

“…This is consistent with other studies where the endocytosis of transferrin receptors [14,15], β 2 ARs [42] and AT1 angiotensin receptors [18] were measured in the presence of concentrations of wortmannin low enough to prevent nonspecific effects. Other studies have suggested that wortmannin inhibits agonist-induced β 2 AR endocytosis, and that agonistdependent recruitment of a PI 3-kinase to the plasma membrane is important for this process [43]. The discrepancy is most likely due to the different β 2 AR expression methods used.…”

Section: Discussionmentioning

confidence: 98%

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Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Awwad

Iyer

Rosenfeld

et al. 2007

Experimental Cell Research

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Phosphatidylinositol 3-kinase inhibitors have been shown to affect the endocytosis or subsequent intracellular sorting in various receptor systems. Agonist-activated β 2 -adrenergic receptors undergo desensitization by mechanisms that include the phosphorylation, endocytosis and degradation of receptors. Following endocytosis, most internalized receptors are sorted to the cell surface, but some proportion is sorted to lysosomes for degradation. It is not known what governs the ratio of receptors that recycle versus receptors that undergo degradation. To determine if phosphatidylinositol 3-kinases regulate β 2 -adrenergic receptor trafficking, HEK293 cells stably expressing these receptors were treated with the phosphatidylinositol 3-kinase inhibitors LY294002 or wortmannin. We then studied agonist-induced receptor endocytosis and postendocytic sorting, including recycling and degradation of the internalized receptors. Both inhibitors amplified the internalization of receptors after exposure to the β-agonist isoproterenol, which was attributable to the sorting of a significant fraction of receptors to an intracellular compartment from which receptor recycling did not occur. The initial rate of β 2 -adrenergic receptor endocytosis and the default rate of receptor recycling were not significantly altered. During prolonged exposure to agonist, LY294002 slowed the degradation rate of β 2 -adrenergic receptors and caused the accumulation of receptors within rab7-positive vesicles. These results suggest that phosphatidylinositol 3-kinase inhibitors (1) cause a misrouting of β 2 -adrenergic receptors into vesicles that are neither able to efficiently recycle to the surface nor sort to lysosomes, and (2) delays the movement of receptors from late endosomes to lysosomes.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 98%

Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Awwad

Iyer

Rosenfeld

et al. 2007

Experimental Cell Research

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“…Thus, EP 4 receptors undergo rapid, PGE 2 -mediated desensitization (14) and internalization (15); whereas EP 2 receptors do not. Since the internalization of some G-protein-coupled receptors is associated with a transactivation of the MAPK pathway (16,17), it may be supposed that such a mechanism could explain the present findings of selective activation of ERK signaling by the EP 4 receptors. However, in a previous study using human EP 4 receptors expressed in HEK-293 cells, it was found that the phosphorylation of ERKs 1 and 2 was independent of PGE 2 -mediated receptor internalization (18).…”

Section: Induction Of Egr-1 Expression In Ep 4 -Expressing Cells Leadmentioning

confidence: 67%

Prostaglandin E2 Induced Functional Expression of Early Growth Response Factor-1 by EP4, but Not EP2, Prostanoid Receptors via the Phosphatidylinositol 3-Kinase and Extracellular Signal-regulated Kinases

Fujino

Regan

2003

Journal of Biological Chemistry

275

258

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We now report that PGE 2 stimulation of EP 4 receptors, but not EP 2 receptors, leads to phosphorylation of the extracellular signal-regulated kinases (ERKs) through a PI3K-dependent mechanism. Furthermore, this activation of PI3K/ERK signaling by the EP 4 receptors induces the functional expression of early growth response factor-1 (EGR-1). Under the same conditions induction of EGR-1 protein expression was not observed following PGE 2 stimulation of EP 2 receptors. These findings point to important differences in the signaling potential of the EP 2 and EP 4 receptors, which could be significant with respect to the potential involvement of EP 4 receptors in inflammation and cancer.The EP 2 and EP 4 prostanoid receptors are two of the four primary receptor subtypes for prostaglandin E 2 (PGE 2 ).1 Both of these receptors couple to G␣ s and can activate adenylyl cyclase resulting in the increased formation of intracellular cyclic 3,5-adenosine monophosphate (cAMP). Prior to the molecular cloning of these receptors it was thought that the stimulation of adenylyl cyclase by PGE 2 was mediated by a single receptor subtype that was defined pharmacologically as the EP 2 subtype (1). Thus, the first adenylyl cyclase stimulatory EP receptor to be cloned was thought to be the EP 2 subtype, but it was subsequently redefined as the EP 4 subtype (2) when a second adenylyl cyclase stimulatory EP receptor was cloned, which had the expected pharmacology of the EP 2 subtype (3). Surprisingly the EP 2 and EP 4 receptors encoded by these cDNAs only shared ϳ30% amino acid homology and were really no more related to each other than to other prostanoid receptor subtypes (4). In fact, the EP 2 receptor shows a closer phylogenetic relationship to the DP and IP receptors than it does to the EP 4 receptor. The human EP 4 receptor is larger than the human EP 2 (488 amino acids versus 358), which is almost entirely due to a significantly longer carboxyl-terminal domain (155 versus 34 amino acids).Recently we have shown that PGE 2 stimulation of the EP 2

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“…To date, the specific cellular function that is associated with GRKs is GPCR phosphorylation and desensitization; recent findings unveil that GRKs are able to interact with nonreceptor proteins (PI3K, AKT, and MEK), suggesting new cellular functions for these kinases (16,(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

The G-protein-coupled receptor kinase 5 inhibits NFκB transcriptional activity by inducing nuclear accumulation of IκBα

Sorriento

Ciccarelli

Santulli

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

107

142

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G-protein-coupled receptor (GPCR) kinases, GRKs, are known as serine/threonine kinases that regulate GPCR signaling, but recent findings propose functions for these kinases besides receptor desensitization. Indeed, GRK5 can translocate to the nucleus by means of a nuclear localization sequence, suggesting that this kinase regulates transcription events in the nucleus. To evaluate the effect of GRK5-IB␣ interaction on NFB signaling, we induced the overexpression and the knockdown of GRK5 in cell cultures. GRK5 overexpression causes nuclear accumulation of IB␣, leading to the inhibition of NFB transcriptional activity. Opposite results are achieved by GRK5 knockdown through siRNA. A physical interaction between GRK5 and IB␣, rather than phosphorylative events, appears as the underlying mechanism. We identify the regulator of gene protein signaling homology domain of GRK5 (RH) and the N-terminal domain of IB␣ as the regions involved in such interaction. To confirm the biological relevance of this mechanism of regulation for NFB, we evaluated the effects of GRK5-RH on NFB-dependent phenotypes. In particular, GRK5-RH overexpression impairs apoptosis protection and cytokine production in vitro and inflammation and tissue regeneration in vivo. Our results reveal an unexpected role for GRK5 in the regulation of NFB transcription activity. Placing these findings in perspective, this mechanism may represent a therapeutic target for all those conditions involving excessive NFB activity.angiogenesis ͉ gene transcription ͉ inflammation ͉ signal transduction G -protein-coupled receptor (GPCR) kinases, GRKs, constitute a large family of serine/threonine protein kinases that regulate GPCR signaling (1-3), consisting of 7 isoforms that share structural and functional similarities (4). A central catalytic domain is flanked by an N-terminal domain that includes a region of homology to regulators of G-protein signaling (RH) and a C-terminal domain of variable length (5, 6). The catalytic domain of GRKs is relatively well-conserved among the members of different subfamilies (Ϸ45% sequence identity), whereas N-terminal RH domains display weak homology (Ϸ27%) and C termini have little or no sequence homology. GRKs have different tissue distribution, subcellular localization, and kinase activity regulation (7,8). GRKs mostly localize at the plasma membrane (2), but recently Johnson et al. (7) demonstrated that GRK4-6 (but not other GRKs) can shuttle between cytosol and nucleus through functional nuclear localization sequence (NLS) and nuclear exporting sequence (NES), thus suggesting a nuclear effect for the GRK4-6 subfamily.NFB is an ubiquitously expressed and highly regulated dimeric transcription factor (3) regulating the expression of genes responsible for innate and adaptive immunity, tissue regeneration, stress responses, apoptosis, cell proliferation, and differentiation (9-14). Within the canonical view of the regulation of the NFB activity, the inactive NFB/IB␣ complex localizes in the cytosol until an extracellular stimulus, ...

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Agonist-dependent Recruitment of Phosphoinositide 3-Kinase to the Membrane by β-Adrenergic Receptor Kinase 1

Cited by 171 publications

References 35 publications

Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

Prostaglandin E2 Induced Functional Expression of Early Growth Response Factor-1 by EP4, but Not EP2, Prostanoid Receptors via the Phosphatidylinositol 3-Kinase and Extracellular Signal-regulated Kinases

The G-protein-coupled receptor kinase 5 inhibits NFκB transcriptional activity by inducing nuclear accumulation of IκBα

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