HIV TAT basic peptide is not a high-affinity ligand for VEGF receptor 2.
The 'transactivator of transcription' (TAT) protein of human immunodeficiency virus transforms cells in culture and promotes the development of tumors, so-called Kaposi's sarcoma, in AIDS patients. TAT induces growth and differentiation of blood vessels and has been suggested to directly activate VEGF receptor 2 expressed on endothelial cells through a peptide sequence located between amino acids 46 and 64, the so-called basic domain. This peptide mimics many aspects of TAT function when added to endothelial cells, even when expressed in the context of recombinant chimeric proteins. To define the exact sites of interaction between this peptide and VEGF receptor 2 we performed binding studies with recombinant proteins derived from the extracellular ligand binding domain of VEGF receptor 2. These in vitro binding studies showed that the TAT peptide binds with only low specificity to Ig-like domain 3 of the receptor, while VEGF interacts with receptor-derived proteins encompassing at least extracellular domains 1 through 3. The original concept that the angiogenic properties of TAT basic peptide result from specific, high-affinity interaction with VEGF receptor 2 must therefore be revised. Apparently this peptide interacts with cells in multiple ways: by directly activating acidic cell surface-exposed receptors, by releasing extracellular matrix-bound growth factors such as bFGF and VEGF which then bind to their cognate receptors, and by activating intracellular signalling molecules with which basic peptide interacts upon translocation into cells.
Rubio Demirovic
Alma
A
Laboratory for Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institute, CH-5232 Villigen-PSI, Switzerland.
Canadi
Jasna
J
Weiglhofer
Wolfgang
W
Scheidegger
Patrick
P
Jaussi
Rolf
R
Kurt
Ballmer-Hofer
BH
D017104:Bacteriophage M13 / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D003001:Cloning, Molecular; D017931:DNA Primers; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006678:HIV / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus
D017931:DNA Primers; D015696:Gene Products, tat; D008024:Ligands; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; C109668:tat peptide (32-72), Human immunodeficiency virus 1; D040301:Vascular Endothelial Growth Factor Receptor-2