Separating Actin-Dependent Chemokine Receptor Nanoclustering from Dimerization Indicates a Role for Clustering in CXCR4 Signaling and Function

Martínez-Muñoz, Laura; Rodrı́guez-Frade, José Miguel; Barroso, Rubén; Sorzano, Carlos Óscar S.; Torreño-Pina, Juan A.; Santiago, César; Manzo, Carlo; Lucas, Pilar; García‐Cuesta, Eva M.; Gutierrez, Enric; Barrio, Laura; Vargas, Javier; Cascio, Graciela; Carrasco, Yolanda R.; Sánchez-Madrid, Francisco; García‐Parajó, María F.; Mellado, Mario

doi:10.1016/j.molcel.2018.02.034

Cited by 80 publications

(115 citation statements)

References 73 publications

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“…CXCR4 is a 352 amino acid rhodopsin-like GPCR, comprising an extracellular N-terminal domain, 7 transmembrane (TM) helices, 3 extra-cellular loops (ECL), 3 intra-cellular loops (ICL) and an intracellular C-terminal domain ( 6 ). CXCR4 can exist in the plasma membrane as a monomer, dimer, higher-order oligomer or nanoclusters ( 7 ), although the partitioning and relevance of these different multimerization states has not been addressed in vivo . Several crystal structures of CXCR4 bound to agonists and small molecules are in accordance with the ability of CXCR4 to form homodimers via interactions of the TM5 and TM6 helices ( 6 ).…”

Section: Cxcr4 and Its Ligandsmentioning

confidence: 99%

“…Several crystal structures of CXCR4 bound to agonists and small molecules are in accordance with the ability of CXCR4 to form homodimers via interactions of the TM5 and TM6 helices ( 6 ). TM6 is also implicated in nanoclustering ( 7 ). CXCR4 can also form heterodimers with ACKR3 (a related GCPR also known as CXCR7), which have distinctive signaling properties ( 8 ).…”

Section: Cxcr4 and Its Ligandsmentioning

confidence: 99%

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The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

2020

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The CXCR4 receptor upon binding its ligands triggers multiple signaling pathways that orchestrate cell migration, hematopoiesis and cell homing, and retention in the bone marrow. However, CXCR4 also directly controls cell proliferation of non-hematopoietic cells. This review focuses on recent reports pointing to its pivotal role in tissue regeneration and stem cell activation, and discusses the connection to the known role of CXCR4 in promoting tumor growth. The mechanisms may be similar in all cases, since regeneration often recapitulates developmental processes, and cancer often exploits developmental pathways. Moreover, cell migration and cell proliferation appear to be downstream of the same signaling pathways. A deeper understanding of the complex signaling originating from CXCR4 is needed to exploit the opportunities to repair damaged organs safely and effectively.

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Section: Cxcr4 and Its Ligandsmentioning

confidence: 99%

Section: Cxcr4 and Its Ligandsmentioning

confidence: 99%

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

2020

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“…The stoichiometry of the different forms could also vary according to cell type and among different patients, possibly contributing to the phenotypic heterogeneity observed in different patients with the same pedigree. Moreover, it has recently been reported that in addition to the ligand-mediated conformational change of the receptor that activates G proteins, CXCR4 undergoes changes associated with receptor nanoclustering that are necessary for signaling and could establish a new target for potential intervention in WHIM and WM patients [81]. A deeper understanding of the functional and pharmacological properties of CXCR4 heterodimers may therefore indicate more specific targets for drug design and development.…”

Section: Effect Of Homo or Heterodimerization On Whim-mutated Cxcr4 Smentioning

confidence: 99%

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

Milanesi

Locati

Borroni

2020

IJMS

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Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom’s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention.

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“…For instance, chemokines are capable of forming dimers and oligomers (15–17), and can interact with synergy-inducing molecules (18) and with glycosaminoglycans (GAGs) (17, 19, 20). It is also known that chemokine receptors are not only monomeric entities, but also exist as dimers and higher-order oligomers (21) that also interact with other membrane proteins (21–24) and exhibit signaling crosstalk with other proteins (25, 26).…”

Section: Introductionmentioning

confidence: 99%

The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases

et al. 2019

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Chemokine receptors are members of the G protein-coupled receptor superfamily. These receptors are intimately involved in cell movement, and thus play a critical role in several physiological and pathological situations that require the precise regulation of cell positioning. CXCR4 is one of the most studied chemokine receptors and is involved in many functions beyond leukocyte recruitment. During embryogenesis, it plays essential roles in vascular development, hematopoiesis, cardiogenesis, and nervous system organization. It has been also implicated in tumor progression and autoimmune diseases and, together with CD4, is one of the co-receptors used by the HIV-1 virus to infect immune cells. In contrast to other chemokine receptors that are characterized by ligand promiscuity, CXCR4 has a unique ligand—stromal cell-derived factor-1 (SDF1, CXCL12). However, this ligand also binds ACKR3, an atypical chemokine receptor that modulates CXCR4 functions and is overexpressed in multiple cancer types. The CXCL12/CXCR4/ACKR3 axis constitutes a potential therapeutic target for a wide variety of inflammatory diseases, not only by interfering with cell migration but also by modulating immune responses. Thus far, only one antagonist directed against the ligand-binding site of CXCR4, AMD3100, has demonstrated clinical relevance. Here, we review the role of this ligand and its receptors in different autoimmune diseases.

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Separating Actin-Dependent Chemokine Receptor Nanoclustering from Dimerization Indicates a Role for Clustering in CXCR4 Signaling and Function

Cited by 80 publications

References 73 publications

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases

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