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1.
PLoS One ; 12(3): e0173486, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28267793

RESUMO

The CXC-chemokine receptor 6 (CXCR6) is a class A GTP-binding protein-coupled receptor (GPCRs) that mediates adhesion of leukocytes by interacting with the transmembrane cell surface-expressed chemokine ligand 16 (CXCL16), and also regulates leukocyte migration by interacting with the soluble shed variant of CXCL16. In contrast to virtually all other chemokine receptors with chemotactic activity, CXCR6 carries a DRF motif instead of the typical DRY motif as a key element in receptor activation and G protein coupling. In this work, modeling analyses revealed that the phenylalanine F3.51 in CXCR6 might have impact on intramolecular interactions including hydrogen bonds by this possibly changing receptor function. Initial investigations with embryonic kidney HEK293 cells and further studies with monocytic THP-1 cells showed that mutation of DRF into DRY does not influence ligand binding, receptor internalization, receptor recycling, and protein kinase B (AKT) signaling. Adhesion was slightly decreased in a time-dependent manner. However, CXCL16-induced calcium signaling and migration were increased. Vice versa, when the DRY motif of the related receptor CX3CR1 was mutated into DRF the migratory response towards CX3CL1 was diminished, indicating that the presence of a DRF motif generally impairs chemotaxis in chemokine receptors. Transmembrane and soluble CXCL16 play divergent roles in homeostasis, inflammation, and cancer, which can be beneficial or detrimental. Therefore, the DRF motif of CXCR6 may display a receptor adaptation allowing adhesion and cell retention by transmembrane CXCL16 but reducing the chemotactic response to soluble CXCL16. This adaptation may avoid permanent or uncontrolled recruitment of inflammatory cells as well as cancer metastasis.


Assuntos
Adaptação Biológica , Motivos de Aminoácidos , Adesão Celular , Receptores de Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Receptores Virais/química , Receptores Virais/metabolismo , Sequência de Aminoácidos , Sinalização do Cálcio , Linhagem Celular , Membrana Celular , Movimento Celular , Quimiotaxia , Expressão Gênica , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CXCR6 , Receptores de Quimiocinas/genética , Receptores Virais/genética , Transdução de Sinais
2.
Oncotarget ; 6(31): 31295-312, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26378057

RESUMO

Syndecan-1 is a surface expressed heparan sulphate proteoglycan, which is upregulated by several tumor types and involved in tumor cell migration and metastasis. Syndecan-1 is shed from the cell surface and the remaining transmembrane fragment undergoes intramembrane proteolysis by γ-secretase. We here show that this generates a cytoplasmic C-terminal fragment (cCTF). In epithelial lung tumor A549 cells the endogenously produced cCTF accumulated when its proteasomal degradation was blocked with bortezomib and this accumulation was prevented by γ-secretase inhibition. Overexpression of the cCTF suppressed migration and invasion of A549 cells. This inhibitory effect was only seen when endogenous Syndecan-1 was present, but not in Syndecan-1 deficient cells. Further, overexpression of Syndecan-1 cCTF increased the basal activation of Src kinase, focal adhesion kinase (FAK) and Rho GTPase. This was associated with increased adhesion to fibronectin and collagen G and an increased recruitment of paxillin to focal adhesions. Moreover, lung tumor formation of A549 cells in mice was reduced by overexpression of Syndecan-1 cCTF. Finally, delivery of a synthetic peptide corresponding to the Syndecan-1 cCTF suppressed A549 cell migration and increased basal phosphorylation of Src and FAK. Our data indicate that the Syndecan-1 cCTF antagonizes Syndecan-1 dependent tumor cell migration in vitro and in vivo by dysregulating proadhesive signaling pathways and suggest that the cCTF can be used as an inhibitory peptide.


Assuntos
Movimento Celular , Proliferação de Células , Citoplasma/metabolismo , Neoplasias Pulmonares/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Proteólise , Sindecana-1/antagonistas & inibidores , Animais , Apoptose , Western Blotting , Adesão Celular , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos SCID , Fosforilação , Transdução de Sinais , Sindecana-1/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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