Syndecan-1 increases B-lymphoid cell extravasation in response to HIV-1 Tat via αvβ3/pp60src/pp125FAK pathway.
Syndecan-1 is a heparan sulfate proteoglycan (HSPG) commonly upregulated in AIDS-related B lymphoid malignancies. Tat is the main HIV-1 transactivating factor that has a major role in the pathogenesis of AIDS-related lymphomas (ARL) by engaging heparan sulfate proteoglycans (HSPGs), chemokine receptors and integrins at the lymphoid cell (LC) surface. Here B-lymphoid Namalwa cell clones that do not express or overexpress syndecan-1 (EV-Ncs and SYN-Ncs, respectively) were compared for their responsiveness with Tat: in the absence of syndecan-1, Tat induces a limited EV-Nc migration via C-X-C motif chemokine receptor 4 (CXCR4), G-proteins and Rac. Syndecan-1 overexpression increases SYN-Nc responsiveness to Tat and makes this response independent from CXCR4 and G-protein and dependent instead on pp60src phosphorylation. Tat-induced SYN-Nc migration and pp60src phosphorylation require the engagement of αvβ3integrin and consequent pp125FAK phosphorylation. This complex set of Tat-driven activations is orchestrated by the direct interaction of syndecan-1 with pp60src and its simultaneous coupling with αvβ3. The Tat/syndecan-1/αvβ3interplay is retained in vivo and is shared also by other syndecan-1+B-LCs, including BJAB cells, whose responsiveness to Tat is inhibited by syndecan-1 knockdown. In conclusion, overexpression of syndecan-1 confers to B-LCs an increased capacity to migrate in response to Tat, owing to a switch from a CXCR4/G-protein/Rac to a syndecan-1/αvβ3/pp60src/pp125FAK signal transduction pathway that depends on the formation of a complex in which syndecan-1 interacts with Tat via its HS-chains, with αvβ3via its core protein ectodomain and with pp60src via its intracellular tail. These findings have implications in ARL progression and may help in identifying new therapeutical targets for the treatment of AIDS-associated neoplasia.
Section of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Urbinati
Section of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Grillo
Section of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Chiodelli
Section of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Tobia
Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Caccuri
Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Fiorentini
Department of Human Genetics, University of Leuven and Flanders Institute for Biotechnology, Leuven, Belgium.
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David
Section of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Rusnati
D002448:Cell Adhesion / Q000235:genetics; D051417:Focal Adhesion Kinase 1 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D053668:Syndecan-1 / Q000235:genetics*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000378:metabolism
C527276:CXCR4 protein, human; D039302:Integrin alphaVbeta3; D046912:Multiprotein Complexes; D019718:Receptors, CXCR4; D053668:Syndecan-1; D054322:tat Gene Products, Human Immunodeficiency Virus; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src)