Interaction of Tyrosine-Based Sorting Signals with Clathrin-Associated Proteins

Ohno, Hiroshi; Stewart, Jay M.; Fournier, Marie-Christine; Bosshart, Herbert; Rhee, Ina; Miyatake, Shoichiro; Saito, Takashi; Gallusser, Andreas; Kirchhausen, Tomas; Bonifacino, Juan S.

doi:10.1126/science.7569928

Cited by 894 publications

(904 citation statements)

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“…The β-subunit of AP-2 also interacts with clathrin and is able to promote clathrin lattice assembly (36). The μ-subunit of AP-2 recognizes the tyrosine-based internalization signals within the cytoplasmic domain of some receptors (37), while the function of the σ chain remains unclear. Both α-and β-subunits of AP-2 are shown to interact with CXCR2 in the present study.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Motif in the Carboxyl Terminus of CXCR2 That Is Involved in Adaptin 2 Binding and Receptor Internalization

et al. 2000

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Agonist treatment of cells expressing the chemokine receptor, CXCR2, induces receptor phosphorylation and internalization through a dynamin-dependent mechanism. In the present study, we demonstrate that a carboxyl terminus-truncated mutant of CXCR2 (331T), which no longer undergoes agonist-induced phosphorylation, continues to undergo ligand-induced internalization in HEK293 cells. This mutant receptor exhibits reduced association with β-arrestin 1 but continues to exhibit association with adaptin 2 α and β subunits. Replacing Leu320-321 and/or Ile323-Leu324 with Ala (LL320,321AA, IL323,324AA, and LLIL320,321,323,324AAAA) in wild-type CXCR2 or 331T causes little change in ligand binding and signaling through Ca 2+ mobilization but greatly impairs the agonist-induced receptor sequestration and ligand-mediated chemotaxis. The LL320,321AA, IL323,324AA, and LLIL320,321,323,324AAAA mutants of CXCR2 exhibit normal binding to β-arrestin 1 but exhibit decreased binding to adaptin 2α and β. These data demonstrate a role for the LLKIL motif in the carboxyl terminus of CXCR2 in receptor internalization and cell chemotaxis and imply a role for adaptin 2 in the endocytosis of CXCR2.The chemokine receptor, CXCR2, 1 is a member of a superfamily of G protein-coupled seventransmembrane receptors (GPCRs) that transduce intracellular signals via heterotrimeric guanine nucleotide-binding proteins (G proteins). Upon stimulation by agonists, such as interleukin 8 (IL-8) or melanoma growth-stimulatory activity (MGSA)/growth-regulatory protein (GRO), CXCR2 activates a series of G protein-mediated events, including phosphatidylinositide hydrolysis, to generate inositol 1,4,5-trisphosphate and diacylglycerol, as well as mobilization of intracellular free Ca 2+ to initiate a series of cellular responses (1). In addition, CXCR2 mediates cell chemotaxis, a distinct function of chemokine receptors (2). Like many other types of GPCRs, CXCR2 undergoes a dynamic trafficking between the cell surface and the intracellular compartments (3). Such trafficking may be involved in both transmission and termination of the receptor signals and may play an important role in mediating cell chemotaxis. For CXCR2, the most remarkable trafficking process is agonistinduced receptor internalization. 1 Abbreviations: CXCR2, receptor for CXC chemokines formerly defined as interleukin 8 receptor B; IL-8, interleukin 8; MGSA/GRO, melanoma growth-stimulatory activity/growth-regulatory protein; GPCRs, G protein-coupled receptors; G proteins, guanine nucleotidebinding proteins; β2-AR, β2-adrenergic receptor; AP-2, adaptin 2; HEK293 cells, human embryonic kidney 293 cells; RBL-2H3 cells, rabbit basophilic leukemia cells; DSP, dithiobis(succinimido propionate); GRKs, G protein-coupled receptor kinases; FITC, fluorescein isothiocyanate; BSA, bovine serum albumin; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; PBS, phosphatebuffered saline; SDS, sodium dodecyl sulfate. Agonist-induced phosphorylation of the carboxyl terminus by G protein-couple...

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Section: Discussionmentioning

confidence: 99%

Identification of a Motif in the Carboxyl Terminus of CXCR2 That Is Involved in Adaptin 2 Binding and Receptor Internalization

et al. 2000

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“…Basolateral sorting is guided by basolateral sorting signals (Keller and Simons, 1997;Rodriguez-Boulan et al, 2005), and they include: short tyrosine motifs such as Yxxf or NPXY (Brewer and Roth, 1991;Le Bivic et al, 1991;Matter et al, 1992), dileucine (Hunziker and Fumey, 1994) or monoleucine motifs with nearby acidic patches (Deora et al, 2004), PxxP, found in EGFR and pleomorphic motifs that do not yet fall into established classes, found in NCAM (Le Gall et al, 1994), transferrin receptor (Odorizzi and Trowbridge, 1997) and polymeric IgA receptor (Aroeti and Mostov, 1994) ( Figure 2). Yeast 2 and 3 hybrid assays (Ohno et al, 1995;Janvier et al, 2003) demonstrated that Yxxf motifs interact with the m subunit of AP adaptors (AP1, AP2, AP3, AP4), whereas dileucine motifs of the type [DE]XXXL [LI] bind to g and s1 subunits of AP1 and to d and s3 subunits of AP3 (Kirchhausen, 2000;Bonifacino and Traub, 2003). Crystallographic studies have elucidated details of some of these interactions, for example, of the AP m subunits with tyrosine motifs and of GGAs (Golgi-localized, g-ear containing, Arf-binding protein) with dileucine motifs in Man6PR (Bonifacino, 2004;Owen et al, 2004).…”

Section: Polarized Trafficking Machinerymentioning

confidence: 99%

The epithelial polarity program: machineries involved and their hijacking by cancer

2008

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The Epithelial Polarity Program (EPP) adapts and integrates three ancient cellular machineries to construct an epithelial cell. The polarized trafficking machinery adapts the cytoskeleton and ancestral secretory and endocytic machineries to the task of sorting and delivering different plasma membrane (PM) proteins to apical and basolateral surface domains. The domain-identity machinery builds a tight junctional fence (TJ) between apical and basolateral PM domains and adapts ancient polarity proteins and polarity lipids on the cytoplasmic side of the PM, which have evolved to perform a diversity of polarity tasks across cells and species, to provide 'identity' to each epithelial PM domain. The 3D organization machinery utilizes adhesion molecules as positional sensors of other epithelial cells and the basement membrane and small GTPases as integrators of positional information with the activities of the domain-identity and polarized trafficking machineries. Cancer is a disease mainly of epithelial cells (90% of human cancers are carcinomas that derive from epithelial cells) that hijacks the EPP machineries, resulting in loss of epithelial polarity, which often correlates in extent with the aggressiveness of the tumor. Here, we review how the EPP integrates its three machineries and the strategies used by cancer to hijack them.

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“…Tyrosine-containing motifs in the C-terminal tails of the receptors for epidermal growth factor, asialoglycoproteins and polymeric immunoglobulins interact directly with the clathrin-associated adaptor protein complex AP-2 [167,168]. The µ2-chain of AP-2 interacts with the Ser-Asp-Tyr-Gln-Arg-Leu motif of the Cterminal tail of the integral membrane protein TGN38 (TGN l trans-Golgi network), as well as with similar motifs from lamp-1, CD68, H2-Mb (histocompatibility Class 2 gene Mb) and the transferrin receptor [169]. The importance of this interaction has recently been questioned by the finding that deletion of the AP-2 binding site of the epidermal growth factor receptor abolishes AP-2 binding to the receptor without affecting internalization [170].…”

Section: Domains Involved In Receptor Endocytosismentioning

confidence: 99%

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Böhm

Grady

Bunnett

1997

Biochemical Journal

474

322

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The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neurotransmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and downregulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from

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Interaction of Tyrosine-Based Sorting Signals with Clathrin-Associated Proteins

Cited by 894 publications

References 32 publications

Identification of a Motif in the Carboxyl Terminus of CXCR2 That Is Involved in Adaptin 2 Binding and Receptor Internalization

Identification of a Motif in the Carboxyl Terminus of CXCR2 That Is Involved in Adaptin 2 Binding and Receptor Internalization

The epithelial polarity program: machineries involved and their hijacking by cancer

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

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