Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells.
Kaposi's sarcoma (KS) spindle cell growth and spread have been reported to be modulated by various cytokines as well as the human immunodeficiency virus (HIV) gene product Tat. Recently, HIV-1 Tat has been shown to act like a cytokine and bind to the Flk-1/KDR receptor for the vascular endothelial growth factor A (VEGF-A), which is expressed by KS cells. We have characterized signal transduction pathways stimulated by HIV-1 Tat upon its binding to surface receptors on KS cells. We observed that stimulation in KS 38 spindle cells resulted in tyrosine phosphorylation and activation of the Flk-1/KDR receptor. We also report that HIV-1 Tat treatment enhanced the phosphorylation and association of proteins found in focal adhesions, such as the related adhesion focal tyrosine kinase RAFTK, paxillin, and p130(cas). Further characterization revealed the activation of mitogen-activated protein kinase, c-Jun amino-terminal kinase (JNK), and Src kinase. HIV-1 Tat contains a basic domain which can interact with growth factor tyrosine kinase receptors and a classical RGD sequence which may bind to and activate the surface integrin receptors for fibronectin and vitronectin. We observed that stimulation of KS cells with basic as well as RGD sequence-containing Tat peptides resulted in enhanced phosphorylation of RAFTK and activation of MAP kinase. These studies reveal that Tat stimulation activates a number of signal transduction pathways that are associated with cell growth and migration.
Ganju
R K
RK
Divisions of Experimental Medicine and Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA.
Munshi
N
N
Nair
B C
BC
Liu
Z Y
ZY
Gill
P
P
Groopman
J E
JE
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D050719:Crk-Associated Substrate Protein; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009842:Oligopeptides / Q000502:physiology; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D050717:Retinoblastoma-Like Protein p130; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D003598:Cytoskeletal Proteins; D015696:Gene Products, tat; D009842:Oligopeptides; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D011506:Proteins; D017978:Receptors, Growth Factor; D050717:Retinoblastoma-Like Protein p130; D054322:tat Gene Products, Human Immunodeficiency Virus; D014443:Tyrosine; C047981:arginyl-glycyl-aspartic acid; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D051418:Focal Adhesion Kinase 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases