HUMAN-IMMUNODEFICIENCY-VIRUS TAT MODULATES THE FLK-1 KDR RECEPTOR, MITOGEN-ACTIVATED PROTEIN-KINASES, AND COMPONENTS OF FOCAL ADHESION IN KAPOSIS-SARCOMA CELLS/

Kaposi's sarcoma (KS) spindle cell growth and spread have been reporte d to be modulated by various cytokines as well as the human immunodefi ciency virus (HIV) gene product Tat. Recently, HIV-1 Tat has been show n to act like a cytokine and bind to the Flk-1/KDR receptor for the va scular endothelial growth factor A (VEGF-A), which is expressed by KS cells. We have characterized signal transduction pathways stimulated b y HIV-1 Tat upon its binding to surface receptors on KS cells. We obse rved that stimulation in KS 38 spindle cells resulted in tyrosine phos phorylation and activation of the Flk-1/KDR receptor. We also report t hat HIV-1 Tat treatment enhanced the phosphorylation and association o f proteins found in focal adhesions, such as the related adhesion foca l tyrosine kinase RAFTK, paxillin, and p130(cas). Further characteriza tion revealed the activation of mitogen-activated protein kinase, c-Ju n amino-terminal kinase (JNK), and Src kinase, HIV-1 Tat contains a ba sic domain which can interact with growth factor tyrosine kinase recep tors and a classical RGD sequence which may bind to and activate the s urface integrin receptors for fibronectin and vitronectin, We observed that stimulation of KS cells with basic as well as RGD sequence-conta ining Tat peptides resulted in enhanced phosphorylation of RAFTK and a ctivation of MAP kinase, These studies reveal that Tat stimulation act ivates a number of signal transduction pathways that are associated wi th cell growth and migration.