THE FPS FES PROTEIN-TYROSINE KINASE PROMOTES ANGIOGENESIS IN TRANSGENIC MICE/

The fps/fes proto-oncogene encodes a cytoplasmic protein-tyrosine kina se known to be highly expressed in hematopoietic cells. To investigate fps/fes biological function, an activating mutation was introduced in to the human fps/fes gene which directs amino-terminal myristylation o f the Fps/Fes protein. This mutant, myristylated protein induced trans formation of Rat-2 fibroblasts. The mutant fps/fes allele was incorpor ated into the mouse germ line and was found to be appropriately expres sed in transgenic mice, in a tissue-specific pattern indistinguishable from that of the endogenous mouse gene. These mice displayed widespre ad hypervascularity, progressing to multifocal hemangiomas. High level of both the transgenic human and endogenous murine fps/fes transcript s were detected in vascular tumors by using RNase protection, and fps/ fes transcripts were localized to endothelial cells of both the vascul ar tumors and normal blood vessels by in situ RNA hybridization. Prima ry human umbilical vein endothelial cultures were also shown to expres s fps/fes transcripts and the Fps/Fes tyrosine kinase. These results i ndicate that fps/fes expression is intrinsic to cells of the vascular endothelial lineage and suggest a direct role of the Fps/Fes protein-t yrosine kinase in the regulation of angiogenesis.