HIV-1 Tat regulates endothelial cell cycle progression via activation of the Ras/ERK MAPK signaling pathway.
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 alpha5beta1 and alphavbeta3 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.
Toschi
Elena
E
AIDS National Center, Istituto Superiore di Sanità, 00161 Rome, Italy.
Bacigalupo
Ilaria
I
Strippoli
Raffaele
R
Chiozzini
Chiara
C
Cereseto
Anna
A
Falchi
Mario
M
Nappi
Filomena
F
Sgadari
Cecilia
C
Barillari
Giovanni
G
Mainiero
Fabrizio
F
Ensoli
Barbara
B
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000821:virology; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D010766:Phosphorylation; D012514:Sarcoma, Kaposi / Q000201:enzymology / Q000821:virology*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D018631:ras Proteins / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D015696:Gene Products, tat; D009842:Oligopeptides; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D054322:tat Gene Products, Human Immunodeficiency Virus; C047981:arginyl-glycyl-aspartic acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins