Flt-1, a receptor for vascular endothelial growth factor, has transforming and morphogenic potentials

Abstract

A paradox of Flt-1, a tyrosine kinase receptor for vascular endothelial growth factor (VEGF), is that the ligand cannot activate the receptor to stimulate growth of cells that exogenously overexpress the receptor. In order to find Flt-1 kinase-dependent biological systems, we obtained for the first time activated forms of the Flt-1 kinase in a ligand-independent manner. Replacement of the ABL sequences in the human leukemia oncoprotein BCR–ABL with the cytoplasmic domain of Flt-1 (BCR–FLT) followed by a retroviral random mutagenesis scheme gave constitutively active artificial chimera BCR–FLTm with mutations within the Flt-1 sequence. Like BCR–ABL it could, but not the original BCR–FLT, transform Rat1 fibroblasts, abrogate cytokine dependence in Ba/F3 cells, and induce neurite-like structures in neuronal PC12 cells. Interestingly, Rat1 cells transformed by BCR–FLTm formed tube-like structures in basement membrane matrix. BCR–FLTm retroviruses may be a very useful tool to investigate an as yet uncovered functions of the Flt-1 kinase.