Fibronectin modulates the effects of HIV-1 Tat on the growth of murine Kaposi's sarcoma-like cells through the down-regulation of tyrosine phosphorylation.
HIV-1 Tat plays a role in the pathogenesis of Kaposi's sarcoma. We therefore investigated the effect of Tat on the growth of murine Kaposi's sarcoma-like spindle (TTB) cells derived from dermal lesions. We observed that Tat and a peptide corresponding to the carboxyl-terminal region (Tat65-80) containing an RGD sequence inhibit TTB cell proliferation only when cells are cultured on fibronectin. This inhibitory effect correlates with redistribution of the alpha(v) integrin subunit on the surface of TTB cells and with down-regulation of tyrosine phosphorylation of specific substrates due to an increased tyrosine phosphatase activity. Indeed, phenylarsine oxide, a potent inhibitor of phosphotyrosine phosphatases, prevented the effects of Tat on TTB cells. We therefore argue that the action of Tat on TTB cells is mediated by the RGD motif through an integrin-based cell signaling pathway involving the activity of phosphotyrosine phosphatase(s), which would lead to a decrease in the levels of phosphotyrosine-containing proteins, among which is erk-2/p42MAPK.
Wu
Z
Z
Department of Biological and Technicological Research, San Rafaele Scientific Institute, Milan, Italy.
Cavallaro
U
U
Marchisio
P C
PC
Soria
M R
MR
Maier
J A
JA
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001152:Arsenicals / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000502:physiology*; D019084:Fluorescent Antibody Technique, Indirect; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1; D039564:Integrin alphaV; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D011233:Precipitin Tests; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D054322:tat Gene Products, Human Immunodeficiency Virus
D015703:Antigens, CD; D001152:Arsenicals; D004791:Enzyme Inhibitors; D005353:Fibronectins; D015696:Gene Products, tat; D039564:Integrin alphaV; D019012:Integrin beta1; D054322:tat Gene Products, Human Immunodeficiency Virus; C029341:oxophenylarsine; D019950:Mitogen-Activated Protein Kinase 1; D017027:Protein Tyrosine Phosphatases