The E3 Ubiquitin Ligase AIP4 Mediates Ubiquitination and Sorting of the G Protein-Coupled Receptor CXCR4

Marchese, Adriano; Raiborg, Camilla; Santini, Francesca; Keen, James H.; Stenmark, Harald; Benovic, Jeffrey L.

doi:10.1016/s1534-5807(03)00321-6

Cited by 359 publications

(493 citation statements)

References 43 publications

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“…A rigorous study from the Raz group demonstrated in vivo that in zebrafish CXCR4 internalization is dispensable for cell motility and directional chemokine sensing, but essential for fine-tuning of migration allowing precise arrival of primordial germ cells [26]. Finally, CXCR4 internalization and its subsequent lysosomal degradation have also been reported [27], a mechanism that is implicated in rendering cells insensitive to chemokines and hence immobile.…”

Section: Keeping Chemotactic Receptors In Placementioning

confidence: 99%

On the move: endocytic trafficking in cell migration

Maritzen

Schachtner

Legler

2015

Cell. Mol. Life Sci.

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Directed cell migration is a fundamental process underlying diverse physiological and pathophysiological phenomena ranging from wound healing and induction of immune responses to cancer metastasis. Recent advances reveal that endocytic trafficking contributes to cell migration in multiple ways. (1) At the level of chemokines and chemokine receptors: internalization of chemokines by scavenger receptors is essential for shaping chemotactic gradients in tissue, whereas endocytosis of chemokine receptors and their subsequent recycling is key for maintaining a high responsiveness of migrating cells. (2) At the level of integrin trafficking and focal adhesion dynamics: endosomal pathways do not only modulate adhesion by delivering integrins to their site of action, but also by supplying factors for focal adhesion disassembly. (3) At the level of extracellular matrix reorganization: endosomal transport contributes to tumor cell migration not only by targeting integrins to invadosomes but also by delivering membrane type 1 matrix metalloprotease to the leading edge facilitating proteolysis-dependent chemotaxis. Consequently, numerous endocytic and endosomal factors have been shown to modulate cell migration. In fact key modulators of endocytic trafficking turn out to be also key regulators of cell migration. This review will highlight the recent progress in unraveling the contribution of cellular trafficking pathways to cell migration.

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Section: Keeping Chemotactic Receptors In Placementioning

confidence: 99%

On the move: endocytic trafficking in cell migration

Maritzen

Schachtner

Legler

2015

Cell. Mol. Life Sci.

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“…Residues-Chemokine receptors and other 7TMRs can be targeted to lysosomes by ubiquitination of lysine residues (15)(16)(17). There are two intracellular lysines in D6-Ala6 and D6-340 that are conserved across mammalian D6 sequences.…”

Section: The Reduced Stability Of D6-ala6 Is Dependent On Intracellulmentioning

confidence: 99%

“…D6 trafficking differs from signaling-competent chemokine receptors (and most other 7TMRs) that typically reside at the cell surface and become rapidly internalized only after activation by ligand. Extensive depletion of extracellular chemokines is limited by receptor desensitization and by receptor down-regulation which, in the case of CXC chemokine receptor 4 and other 7TMRs, is driven by monoubiquitination of intracellular lysines and subsequent passage to lysosomes for degradation (15)(16)(17).…”

mentioning

confidence: 99%

Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6

McCulloch¹,

Morrow²,

Milasta

et al. 2008

Journal of Biological Chemistry

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D6 is a heptahelical receptor that suppresses inflammation and tumorigenesis by scavenging extracellular pro-inflammatory CC chemokines. Previous studies suggested this is dependent on constitutive trafficking of stable D6 protein to and from the cell surface via recycling endosomes. By internalizing chemokine each time it transits the cell surface, D6 can, over time, remove large quantities of these inflammatory mediators. We have investigated the role of the conserved 58-amino acid C terminus of human D6, which, unlike the rest of the protein, shows no clear homology to other heptahelical receptors. We show that, in human HEK293 cells, a serine cluster in this region controls the constitutive phosphorylation, high stability, and intracellular trafficking itinerary of the receptor and drives green fluorescent protein-tagged ␤-arrestins to membranes at, and near, the cell surface. Unexpectedly, however, these properties, and the last 44 amino acids of the C terminus, are dispensable for D6 internalization and effective scavenging of the chemokine CCL3. Even in the absence of the last 58 amino acids, D6 still initially internalizes CCL3 but, surprisingly, exposure to ligand inhibits subsequent CCL3 uptake by this mutant. Progressive scavenging is therefore abrogated. We conclude that the heptahelical body of D6 on its own can engage the endocytotic machinery of HEK293 cells but that the C terminus is indispensable for scavenging because it prevents initial chemokine engagement of D6 from inhibiting subsequent chemokine uptake.

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“…Hrs is ubiquitinated itself, and must be deubiquitinated for receptor sorting to the degradative pathway. This ubiquitination status is proposed to be regulated by Vps4 (Marchese et al, 2003b).…”

Section: Endosomal Sorting Of Ubiquitinated Cargomentioning

confidence: 99%