Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1α: implications for development of selective CXCR4 antagonists

Gupta, Shalley K.; Pillarisetti, Kodandaram; Thomas, Roberta; Aiyar, Nambi

doi:10.1016/s0165-2478(01)00228-0

Cited by 76 publications

(70 citation statements)

References 31 publications

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“…Interestingly a similar concentration discrepancy in functional and binding assays has been noted previously for antagonist AMD3100, which inhibits only 30% of binding by radiolabeled SDF-1 to CXCR4 (65). It was later shown that AMD3100 inhibits with high affinity functional responses (chemotaxis and calcium mobilization), whereas it inhibits with much lower (ϳ3000-fold) affinity the binding of radiolabeled SDF-1 to CXCR4 (66).…”

Section: Discussionsupporting

confidence: 71%

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Dubeykovskaya

Dubeykovskiy

Solal-Cohen

et al. 2009

Journal of Biological Chemistry

106

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The secreted trefoil factor family 2 (TFF2) protein contributes to the protection of the gastrointestinal mucosa from injury by strengthening and stabilizing mucin gels, stimulating epithelial restitution, and restraining the associated inflammation. Although trefoil factors have been shown to activate signaling pathways, no cell surface receptor has been directly linked to trefoil peptide signaling. Here we demonstrate the ability of TFF2 peptide to activate signaling via the CXCR4 chemokine receptor in cancer cell lines. We found that both mouse and human TFF2 proteins (at ϳ0.5 M) activate Ca 2؉ signaling in lymphoblastic Jurkat cells that could be abrogated by receptor desensitization (with SDF-1␣) or pretreatment with the specific antagonist AMD3100 or an anti-CXCR4 antibody. TFF2 pretreatment of Jurkat cells decreased Ca 2؉ rise and chemotactic response to SDF-1␣. In addition, the CXCR4-negative gastric epithelial cell line AGS became highly responsive to TFF2 treatment upon expression of the CXCR4 receptor. TFF2-induced activation of mitogen-activated protein kinases in gastric and pancreatic cancer cells, KATO III and AsPC-1, respectively, was also dependent on the presence of the CXCR4 receptor. Finally we demonstrate a distinct proliferative effect of TFF2 protein on an AGS gastric cancer cell line that expresses CXCR4. Overall these data identify CXCR4 as a bona fide signaling receptor for TFF2 and suggest a mechanism through which TFF2 may modulate immune and tumorigenic responses in vivo.

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Section: Discussionsupporting

confidence: 71%

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Dubeykovskaya

Dubeykovskiy

Solal-Cohen

et al. 2009

Journal of Biological Chemistry

106

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“…Based on the differences of IC 50 values of AMD3100 on chemotactic and CXCR4 binding assays of SDF-1␣ as well as the biphasic binding behavior of 125 I-SDF-1␣ on CXCR4-expressing cell lines, it has been proposed that AMD3100 and SDF-1␣ can bind to CXCR4 simultaneously (46). Mutagenesis experiments suggest that the second extracellular loop, transmembrane IV, and transmembrane VI of CXCR4 are critical for its interaction with AMD3100 (47,48).…”

Section: Discussionmentioning

confidence: 99%

Identification of Allosteric Peptide Agonists of CXCR4

Sachpatzidis¹,

Benton²,

Manfredi³

et al. 2003

Journal of Biological Chemistry

120

126

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The chemokine receptor CXCR4 is a co-receptor for T-tropic strains of HIV-1. A number of small molecule antagonists of CXCR4 are in development but all are likely to lead to adverse effects due to the physiological function of CXCR4. To prevent these complications, allosteric agonists may be therapeutically useful as adjuvant therapy in combination with small molecule antagonists. A synthetic cDNA library coding for 160,000 different SDF-based peptides was screened for CXCR4 agonist activity in a yeast strain expressing a functional receptor. Peptides that activated CXCR4 in an autocrine manner induced colony formation. Two peptides, designated RSVM and ASLW, were identified as novel agonists that are insensitive to the CXCR4 antagonist AMD3100. In chemotaxis assays using the acute lymphoblastic leukemia cell line CCRF-CEM, RSVM behaves as a partial agonist and ASLW as a superagonist. The superagonist activity of ASLW may be related to its inability to induce receptor internalization. In CCRF-CEM cells, the two peptides are also not inhibited by another CXCR4 antagonist, T140, or the neutralizing monoclonal antibodies 12G5 and 44717.111. These results suggest that alternative agonist-binding sites are present on CXCR4 that could be screened to develop molecules for therapeutic use.

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“…These cells have been shown to retain CD4, CXCR4, and CCR5 expression and retain CD4 expression unless viral replication is active [138]. Given this observation, the HL-60 and OM-10.1 cell lines have been used in several studies that simply aim at examining the levels of CD4, CXCR4, and CCR5 or other surface markers under various cellular physiological conditions and drug treatments [138,[144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159]. These cells have also been used to screen methodologies or drugs that may inhibit HIV-1 infection or reduce transcriptional activation of the virus [117,[160][161][162][163][164][165][166][167][168][169][170][171][172][173].…”

Section: Hl-60mentioning

confidence: 99%

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Nonnemacher¹,

Quiterio²,

Allen³

et al. 2017

Biology of Myelomonocytic Cells

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Human immunodeficiency virus type 1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), primarily infects T cells and cells of the monocyte-macrophage lineage. This is due to the presence of the cell surface receptor CD4 and the coreceptors, CXCR4, and CCR5. While the T-cell has classically been the cell type associated with HIV-1 disease progression, cells of the monocyte-macrophage lineage have also been shown to play a major role in this viral pathologic process. Classically, this has involved monocytic cells in the peripheral blood and tissue macrophages, however, over the course of HIV disease, the promyelomonocytic cells of the bone marrow (BM) have also been shown to play a role in pathogenesis retroviral disease in that they play an integral role in the reseeding of the periphery and end-organ tissues. This has involved an initial infection of the bone marrow hematopoietic progenitor cells. Given this observation, over the years there have been a number of cell lines that have been developed and provided valuable insights into research questions surrounding HIV-1 infection of the monocyte-macrophage cell lineage. In this regard, we will examine the biological and immunological properties of these BM-derived cell lines with respect to their utility in exploring the pathogenesis of HIV-1 in humans.

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Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1α: implications for development of selective CXCR4 antagonists

Cited by 76 publications

References 31 publications

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Identification of Allosteric Peptide Agonists of CXCR4

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

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