Signaling properties of VEGF receptor-1 and -2 homo- and heterodimers.
Vascular endothelial growth factor (VEGF-A) exerts its effects through receptor tyrosine kinases VEGF receptor-1 (VEGFR-1) and VEGFR-2, which are expressed on most endothelial cell types in vitro and in vivo. We have examined VEGF-A-induced signal transduction in porcine aortic endothelial (PAE) cells individually expressing VEGFR-1 or VEGFR-2, and cells co-expressing both receptor types. We show that VEGF-A-stimulated PAE cells co-expressing VEGFR-1 and -2 contain receptor heterodimers. VEGF-A-stimulation of all three cell lines (expressing VEGFR-1, -2 and -1/2) resulted in signal transduction with different efficiencies. Thus, tyrosine phosphorylation of phospholipase Cgamma, and accumulation of inositol polyphosphates were efficiently transduced in the VEGFR-1/2 cells whereas cells expressing VEGFR-1 responded poorly in these assays. In contrast, VEGF-A-induced activation of phosphoinositide 3-kinase and induction of Ca2+ fluxes were transduced well by VEGFR-1 and VEGFR-2 homo- and heterodimers. The pattern of Ca2+ fluxes was unique for each type of VEGF receptor dimer. Our data show that signal transduction induced by VEGF-A is transduced in distinct manners by homo- and heterodimers of VEGF receptors.
Huang
K
K
Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, S-751 85, Uppsala, Sweden.
Andersson
C
C
Roomans
G M
GM
Ito
N
N
Claesson-Welsh
L
L
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D019281:Dimerization; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D007295:Inositol Phosphates / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000737:chemistry / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction; D013379:Substrate Specificity; D013552:Swine; D010738:Type C Phospholipases / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1
D007295:Inositol Phosphates; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D010738:Type C Phospholipases; D051966:Phospholipase C gamma