Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.
29 Jan 1999-Science (American Association for the Advancement of Science)-Vol. 283, Iss: 5402, pp 655-661
TL;DR: Data suggest that beta-arrestin binding, which terminates receptor-G protein coupling, also initiates a second wave of signal transduction in which the "desensitized" receptor functions as a critical structural component of a mitogenic signaling complex.
Abstract: The Ras-dependent activation of mitogen-activated protein (MAP) kinase pathways by many receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) requires the activation of Src family tyrosine kinases. Stimulation of beta2 adrenergic receptors resulted in the assembly of a protein complex containing activated c-Src and the receptor. Src recruitment was mediated by beta-arrestin, which functions as an adapter protein, binding both c-Src and the agonist-occupied receptor. beta-Arrestin 1 mutants, impaired either in c-Src binding or in the ability to target receptors to clathrin-coated pits, acted as dominant negative inhibitors of beta2 adrenergic receptor-mediated activation of the MAP kinases Erk1 and Erk2. These data suggest that beta-arrestin binding, which terminates receptor-G protein coupling, also initiates a second wave of signal transduction in which the "desensitized" receptor functions as a critical structural component of a mitogenic signaling complex.
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Cites background from "Beta-arrestin-dependent formation o..."
...GRKs and arrestins can serve also as signaling switches, promoting a new wave of signaling events that are G protein-independent (Hall et al., 1999; Luttrell et al., 1999)....
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...However, accumulating evidence suggests that these receptors do not signal exclusively through heterotrimeric G proteins and may also engage in G proteinindependent signaling events (Luttrell et al., 1999; Luttrell and Lefkowitz, 2002)....
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TL;DR: GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.
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Cites background from "Beta-arrestin-dependent formation o..."
...Interestingly, only the full-length b-arrestin2 coprecipitated with GPR120 and TAB1, while a series of deletion/truncation b-arrestin2 mutants did not, indicating that the interactions are dependent on the complete tertiary structure of b-arrestin2 (Figure S2D; Luttrell et al., 1999)....
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Journal Article•
TL;DR: The focus of this review is the current and evolving understanding of the contribution of GRKs, beta-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitized.
Abstract: G protein-coupled receptors (GPCRs) are seven transmembrane proteins that form the largest single family of integral membrane receptors. GPCRs transduce information provided by extracellular stimuli into intracellular second messengers via their coupling to heterotrimeric G proteins and the subsequent regulation of a diverse variety of effector systems. Agonist activation of GPCRs also initiates processes that are involved in the feedback desensitization of GPCR responsiveness, the internalization of GPCRs, and the coupling of GPCRs to heterotrimeric G protein-independent signal transduction pathways. GPCR desensitization occurs as a consequence of G protein uncoupling in response to phosphorylation by both second messenger-dependent protein kinases and G protein-coupled receptor kinases (GRKs). GRK-mediated receptor phosphorylation promotes the binding of beta-arrestins, which not only uncouple receptors from heterotrimeric G proteins but also target many GPCRs for internalization in clathrin-coated vesicles. beta-Arrestin-dependent endocytosis of GPCRs involves the direct interaction of the carboxyl-terminal tail domain of beta-arrestins with both beta-adaptin and clathrin. The focus of this review is the current and evolving understanding of the contribution of GRKs, beta-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitization. In addition to their role as GPCR-specific endocytic adaptor proteins, beta-arrestins also serve as molecular scaffolds that foster the formation of alternative, heterotrimeric G protein-independent signal transduction complexes. Similar to what is observed for GPCR desensitization and resensitization, beta-arrestin-dependent GPCR internalization is involved in the intracellular compartmentalization of these protein complexes.
1,898 citations
Cites background from "Beta-arrestin-dependent formation o..."
...Consistent with the concept that GPCRs activate MAPKs by multiple converging mechanisms, many GPCRs were observed to mediate MAPK activation in manner that was independent of their internalization (Blaukat et al., 1999; Budd et al., 1999; DeGraff et al., 1999; Li et al., 1999; Schramm and Limbird, 1999; Whistler and von Zastrow, 1999)....
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...Consequently, similar to what is observed for GPCR desensitization, differences in b-arrestin-mediated internalization and trafficking of GPCRs may determine distinct patterns of MAPK activation and the mitogenic potential of GPCR activation....
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...The b-arrestin/c-Src interactions involve the association of the b-arrestin amino terminus with the Src homology 1 domain of c-Src (Miller et al., 2000). b-Arrestin mutants defective in their ability to interact with c-Src also effectively blocked b2AR-mediated activation of MAPK (Luttrell et al., 1999b)....
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...In contrast, a PAR2 mutant defective in b-arrestin binding stimulated MAPK activation and cell proliferation....
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...As a consequence, the activation of wild-type PAR2 prevented the translocation of MAPK to the nucleus and by virtue of the fact that MAPK was retained within the cytosol prevented cell proliferation....
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References
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TL;DR: The results show that β-arrestin functions as an adaptor in the receptor-mediated endocytosis pathway, and suggest a general mechanism for regulating the trafficking of G-protein-coupled receptors.
Abstract: The ability of a system to regulate its responsiveness in the presence of a continuous stimulus, often termed desensitization, has been extensively characterized for the beta2-adrenergic receptor (beta2AR). beta2AR signalling is rapidly attenuated through receptor phosphorylation and subsequent binding of the protein beta-arrestin. Ultimately the receptor undergoes internalization, and although the molecular mechanism is unclear, receptor phosphorylation and beta-arrestin binding have been implicated in this processs. Here we report that beta-arrestin and arrestin-3, but not visual arrestin, promote beta2AR internalization and bind with high affinity directly and stoichiometrically to clathrin, the major structural protein of coated pits. Moreover, beta-arrestin/arrestin chimaeras that are defective in either beta2AR or clathrin binding show a reduced ability to promote beta2AR endocytosis. Immunofluorescence microscopy of intact cells indicates an agonist-dependent colocalization of the beta2AR and beta-arrestin with clathrin. These results show that beta-arrestin functions as an adaptor in the receptor-mediated endocytosis pathway, and suggest a general mechanism for regulating the trafficking of G-protein-coupled receptors.
1,294 citations
TL;DR: A mechanism previously shown to mediate uncoupling of the β2-adrenergic receptor from Gs and thus heterologous desensitization (PKA-mediated receptor phosphorylation), also serves to ‘switch’ coupling of this receptor fromGs to Gi and initiate a new set of signalling events.
Abstract: Many of the G-protein-coupled receptors for hormones that bind to the cell surface can signal to the interior of the cell through several different classes of G protein1,2,3,4. For example, although most of the actions of the prototype β2-adrenergic receptor are mediated through Gs proteins and the cyclic-AMP-dependent protein kinase (PKA) system5,6, β-adrenergic receptors can also couple to Gi proteins1,2. Here we investigate the mechanism that controls the specificity of this coupling. We show that in HEK293 cells, stimulation of mitogen-activated protein (MAP) kinase by the β2-adrenergic receptor is mediated by the βγ subunits of pertussis-toxin-sensitive G proteins through a pathway involving the non-receptor tyrosine kinase c-Src and the G protein Ras. Activation of this pathway by the β2-adrenergic receptor requires that the receptor be phosphorylated by PKA because it is blocked by H-89, an inhibitor of PKA. Additionally, a mutant of the receptor, which lacks the sites normally phosphorylated by PKA, can activate adenylyl cyclase5, the enzyme that generates cAMP, but not MAP kinase. Our results demonstrate that a mechanism previously shown to mediate uncoupling of the β2-adrenergic receptor from Gs and thus heterologous desensitization7 (PKA-mediated receptor phosphorylation), also serves to ‘switch’ coupling of this receptor from Gs to Gi and initiate a new set of signalling events.
1,284 citations
TL;DR: Endocytic trafficking of activated EGFR plays a critical role not only in attenuating EGFR signaling but also in establishing and controlling specific signaling pathways.
Abstract: Epidermal growth factor receptor (EGFR) signaling was analyzed in mammalian cells conditionally defective for receptor-mediated endocytosis. EGF-dependent cell proliferation was enhanced in endocytosis-defective cells. However, early EGF-dependent signaling events were not uniformly up-regulated. A subset of signal transducers required the normal endocytic trafficking of EGFR for full activation. Thus, endocytic trafficking of activated EGFR plays a critical role not only in attenuating EGFR signaling but also in establishing and controlling specific signaling pathways.
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TL;DR: The transduction of a signal is a change in form of the signal as it is passed from one carrier to another, and the signal transduction protein must be highly integrated, with all of the elements working together to send just the appropriate quanta of signal for the specific need.
989 citations
TL;DR: Overexpression of β-arrestins in human embryonic kidney cells rescued the sequestration of β2-adrenergic receptor (β2AR) mutants defective in their ability to sequester, an effect enhanced by simultaneous overexpressionof β-adenergic receptor kinase 1 and two β-Arrestin mutants.
Abstract: β-Arrestins are proteins that bind phosphorylated heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) and contribute to the desensitization of GPCRs by uncoupling the signal transduction process Resensitization of GPCR responsiveness involves agonist-mediated receptor sequestration Overexpression of β-arrestins in human embryonic kidney cells rescued the sequestration of β 2 -adrenergic receptor (β 2 AR) mutants defective in their ability to sequester, an effect enhanced by simultaneous overexpression of β-adrenergic receptor kinase 1 Wild-type β 2 AR sequestration was inhibited by the overexpression of two β-arrestin mutants These findings suggest that β-arrestins play an integral role in GPCR internalization and thus serve a dual role in the regulation of GPCR function
962 citations