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Seven-Transmembrane Receptor Signaling Through β-Arrestin

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Science's STKE  01 Nov 2005:
Vol. 2005, Issue 308, pp. cm10
DOI: 10.1126/stke.2005/308/cm10

Abstract

Cell surface receptors are important communicators of external stimuli to the cell interior where they lead to initiation of various signaling pathways and cellular responses. The largest receptor family is the seven-transmembrane receptor (7TMR) family, with approximately 1000 coding genes in the human genome. When 7TMRs are stimulated with agonists, they activate heterotrimeric guanine nucleotide-binding proteins (G proteins), leading to the production of signaling second messengers, such as adenosine 3′,5′-monophosphate, inositol phosphates, and others. Activated receptors are rapidly phosphorylated on serine and threonine residues by specialized enzymes called G protein–coupled receptor kinases. Phosphorylated receptors bind the multifunctional adaptor proteins β-arrestin1 and β-arrestin2 with high affinity. β-arrestin binding blocks further G protein coupling, leading to "desensitization" of G protein–dependent signaling pathways. For several years, this was considered the sole function of β-arrestins. However, novel functions of β-arrestins have been discovered. β-arrestins are now designated as important adaptors that link receptors to the clathrin-dependent pathway of internalization. β-arrestins bind and direct the activity of several nonreceptor tyrosine kinases in response to 7TMR stimulation. β-arrestins also bind and scaffold members of such signaling cascades as the mitogen-activated protein kinases (MAPKs). β-arrestins are crucial components in 7TMR signaling leading to cellular responses that include cell survival and chemotaxis. β-arrestins act as endocytic adaptors and signal mediators not only for the 7TMRs, but also for several receptor tyrosine kinases.

Description

This record contains general information about the Seven-Transmembrane Receptor Signaling Through β-Arrestin collected across species.

Signal transduction by the superfamily of seven-transmembrane receptors [7TMRs, also called heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs)] is modulated by three families of regulatory proteins: G proteins, GPCR kinases (GRKs), and arrestins. Activation of 7TMRs by their agonists promotes conformational changes that lead to activation of G proteins (dissociation of their α and βγ subunits, each of which signals to downstream effectors, such as second messenger–generating enzymes), and ultimately results in changes in cellular physiology.

An important feature of agonist-stimulated 7TMRs is their waning responsiveness to repeated stimulation with agonists, a process termed desensitization. This two-step process involves (i) phosphorylation of receptor intracellular domains by GRKs, and (ii) recruitment of cytosolic arrestin proteins. The mammalian arrestin family is composed of four members: arrestin1 and arrestin4 are confined to retinal rods and cones, respectively, and arrestin2 (also known as β-arrestin1) and arrestin3 (also known β-arrestin2) are ubiquitously distributed and bind most 7TMRs.

Although originally discovered as inhibitors of receptor–G protein coupling, the β-arrestins are now appreciated for their novel roles in endocytosis and signaling by 7TMRs (14). This Pathway serves to highlight the various signaling processes in which β-arrestins participate (Fig. 1). β-arrestins recruit c-Src family nonreceptor tyrosine kinase molecules to form signaling complexes with activated receptors (5, 6) (Table 1). Receptor-bound β-arrestins act as signaling scaffolds for mitogen-activated protein kinase (MAPK) cascades, leading to robust activation of c-Jun N-terminal kinase 3 (JNK3), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38 kinases (714) (Table 2). β-arrestin-dependent ERK activation and p38 activation may be involved in stimulus-driven cell migration (chemotaxis) (10, 1519). β-arrestins stabilize the inhibitor of nuclear factor κB (IκB) protein in the cytosol and thus regulate nuclear factor κB (NF-κB) pathways (20, 21) (Table 1).

Fig. 1.

Pathway image captured from the dynamic graphical display of the information in the Connections Maps available 9 October 2005. For a key to the colors and symbols and to access the underlying data, please visit the pathway (About Connections Map).

Table 1.

Nonreceptor tyrosine kinase pathways and other pathways regulated by β-arrestins in response to 7TMR stimulation. β2AR, beta 2 adrenergic receptor; AT1aR, angiotensin type 1a receptor; CXCR1, chemokine (CXC motif) receptor 1; CXCR2, chemokine (CXC motif) receptor 2; ERK1/2, extracellular signal-regulated kinase 1 and 2; FPR, N-formyl peptide receptor; Fz4R, Frizzled 4 receptor; HEK-293, human embryonic kidney 293 cells; IGF-1R, insulin-like growth factor type 1 receptor; KNRK, Kirsten murine sarcoma virus transformed rat kidney epithelial cells; MDA-MB-231, human breast adenocarcinoma; MEFs, mouse embryonic fibroblasts; NF-κB, nuclear factor κB; NIH3T3, mouse fibroblast cell line originated at the NIH; NK1R, neurokinin 1 receptor; PAR2, protease-activated receptor 2; PI3K, phosphatidylinositol 3-kinase; TNF, tumor necrosis factor; V2R, vasopressin type 2 receptor; VSMC, vascular smooth muscle cells.

Table 2.

MAPK pathways regulated by β-arrestins in response to 7TMR stimulation. AT1aR, angiotensin type 1a receptor; β2AR, beta 2 adrenergic receptor; CCR7, chemokine (C-C motif) receptor 7; COS-7, African monkey kidney cells transformed with SV40; CXCR4, chemokine (CXC motif) receptor 2; ELC, Epstein-Barr virus-induced molecule-1 ligand chemokine; HEK-293, human embryonic kidney 293 cells; ERK, extracellular signal-regulated kinase; JNK, c-Jun amino terminal kinase; IGF-1R, insulin-like growth factor type 1 receptor; MDA-MB-231, human breast adenocarcinoma; MEFs, mouse embryonic cells; NK1R, neurokinin 1 receptor; PAR2, protease-activated receptor 2; PC12, pheochromocytoma 12; PKC, protein kinase C; pERK, phosphorylated ERK; S-49, murine T lymphoma cell line; siRNA, small-interfering RNA; TrK receptor, tropomyosin-related kinase receptor; US28, human cytomegalovirus G protein coupled receptor US28 gene; V2R, vasopressin type 2 receptor.

Mdm2, an oncoprotein and E3 ubiquitin ligase, binds and ubiquitinates β-arrestins upon β2-adrenergic receptor stimulation. Inhibition of this β-arrestin ubiquitination impedes agonist-stimulated receptor internalization (41). β-arrestin ubiquitination is not only required for its endocytotic functions, but also for stable receptor interaction and efficient scaffolding and targeting of phosphorylated ERK (pERK) to endosomal compartments (42, 43). It is predictable that ubiquitination of β-arrestin regulates its multifaceted functions, including signaling.

The roles of β-arrestin are currently expanding beyond the realm of 7TMRs. β-arrestin forms a crucial component in the signaling pathways initiated by insulin-like growth factor 1 (IGF-1) receptor [see the IGF-1 Receptor Signaling through β-Arrestin Pathway (About Connections Map)]. Details about β-arrestin mediated signaling in human embryonic kidney 293 cells in response to angiotensin are also available in the specific pathway (Table 3).

Table 3

Specific examples of the β–arrestin-mediated signaling pathway in the Connections Maps database.

Pathway Details

URL: About Connections Map

Scope: Canonical

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