SIGNALING PROPERTIES OF FLT4, A PROTEOLYTICALLY PROCESSED RECEPTOR TYROSINE KINASE RELATED TO 2 VEGF RECEPTORS

The FLT4, FLT1 and KDR/FLK1 genes encode, structurally similar endothe lial cell receptor tyrosine kinases. Recently it has been shown that t he FLT1 and KDR/FLK-1 proteins function as high-affinity receptors for vascular endothelial growth factor (VEGF). Here we show that FLT4 doe s not act as a receptor for VEGF, as VEGF did not show specific bindin g to the FLT4 tyrosine kinase or induce its autophosphorylation. Also, FLT4 did not interact with KDR in response to VEGF. However, when fus ed with the ligand binding domain of the colony stimulating factor-1 r eceptor (CSF-1R), the FLT4 tyrosine kinase was specifically activated by CSF-1. The activated FLT4 tyrosine kinase domain was found to inter act with the Src homology 2 domains of the SHC and GRB2 adaptor protei ns in vitro and with SHC in cells. CSF-1 stimulation of the CSF-1R/FLT 4 receptor chimera induced thymidine incorporation in serum-starved NI H3T3 fibroblasts, but not in porcine aortic or murine lung capillary e ndothelial cells, although tyrosyl phosphorylation of the receptor and SHC occurred in these cells as well. These results suggest that the e ndothelial cell FLT4 receptor tyrosine kinase transmits signals for an as yet unidentified growth factor.