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Vol. 17, Issue 4, 1985-1994, April 2006

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HIV-1 Tat Regulates Endothelial Cell Cycle Progression via Activation of the Ras/ERK MAPK Signaling Pathway

Elena Toschi ^*, Ilaria Bacigalupo ^*, Raffaele Strippoli , Chiara Chiozzini ^*, Anna Cereseto , Mario Falchi ^*, Filomena Nappi ^*, Cecilia Sgadari ^*, Giovanni Barillari , Fabrizio Mainiero , and Barbara Ensoli ^*

^* AIDS National Center, Istituto Superiore di Sanità, 00161 Rome, Italy; Department of Experimental Medicine and Pathology, Institute Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, 00185 Rome, Italy; Laboratory of Molecular Biology, Scuola Normale Superiore, 56100 Pisa, Italy; and Department of Experimental Medicine, University "Tor Vergata," 00173 Rome, Italy

Submitted August 3, 2005; Revised January 12, 2006; Accepted January 18, 2006
Monitoring Editor: Carl-Henrik Heldin

Tat, the transactivator of HIV-1 gene expression, is released by acutely HIV-1-infected T-cells and promotes adhesion, migration, and growth of inflammatory cytokine-activated endothelial and Kaposi's sarcoma cells. It has been previously demonstrated that these effects of Tat are due to its ability to bind through its arginine-glycine-aspartic (RGD) region to the 51 and v3 integrins. However, the signaling pathways linking Tat to the regulation of cellular functions are incompletely understood. Here, we report that Tat ligation on human endothelial cells results in the activation of the small GTPases Ras and Rac and the mitogen-activated protein kinase ERK, specifically through its RGD region. In addition, we demonstrated that Tat activation of Ras, but not of Rac, induces ERK phosphorylation. We also found that the receptor proximal events accompanying Tat-induced Ras activation are mediated by tyrosine phosphorylation of Shc and recruitment of Grb2. Moreover, Tat enabled endothelial cells to progress through the G1 phase in response to bFGF, and the process is linked to ERK activation. Taken together, these data provide novel evidence about the ability of Tat to activate the Ras-ERK cascade which may be relevant for endothelial cell proliferation and for Kaposi's sarcoma progression.

Abbreviations used: AIDS-KS, acquired immune-deficiency syndrome-associated KS; bFGF, basic fibroblast growth factor; ERK, extracellular signal-related kinase; FN, fibronectin; HIV-1, human immunodeficiency virus-1; HUVEC, human umbilical endothelial cell; KS, Kaposi's sarcoma; MAPK, mitogen-activated protein kinase; RGD, arginine-glycine-aspartic acid.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Barbara Ensoli (ensoli{at}iss.it).

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