Abstract
c-kit receptor tyrosine kinase is a marker of progenitor cells, which differentiate into blood and/or vascular endothelial cells, and has an important role in the amplification/mobilization of progenitor cells. c-kit is expressed in mature endothelial cells, but its role there is unclear. Stem cell factor, a c-kit ligand, dose-dependently promoted survival, migration, and capillary tube formation of human umbilical vein endothelial cells. These effects mimicked those of vascular endothelial growth factor, except that stem cell factor did not sufficiently support proliferation of these cells. After exposing cells to this factor, Akt, Erk1/2, and c-kit were immediately (</=5 min) and dose-dependently tyrosinephosphorylated. STI-571, a c-kit inhibitor, dose-dependently attenuated these phosphorylations and inhibited stem cell factor-promoted survival and capillary tube formation over the same dose range. Wortmannin and LY294002, inhibitors of phosphoinositide 3-kinase, and PD98059, an inhibitor of MEK, abrogated survival and capillary tube formation, indicating that Akt and Erk1/2 should promote survival and capillary tube formation of these endothelial cells at a locus downstream to stem cell factor/c-kit signaling. Akt was more strongly phosphorylated, whereas Erk1/2 and p38 were more weakly phosphorylated with stem cell factor than with vascular endothelial growth factor. Phospholipase Cgamma was phosphorylated only with the latter, indicating that stem cell factor/c-kit signaling is somewhat different.
Highlights
These progenitor cells and mature endothelial cells express several common molecular markers, such as von Willebrand factor, c-kit, Tie-2, Flt-1/VEGF-receptor-1, KDR/ Flk-1/VEGF receptor-2, Sca-1, CXCR4, CD146, CD31, and CD34 [13]
We initially examined whether SCF can drive capillary tube formation of HUVEC in collagen threedimensional culture
Contribution of Akt and Erk1/2 to Capillary Tube Formation in HUVECs Stimulated with SCF or VEGF—Since tyrosine phosphorylation profiles of Akt and Erk1/2 were different in HUVECs treated with SCF and VEGF, we evaluated the contributions of Akt and Erk1/2 in the cells using two kinds of tyrosine kinase inhibitors
Summary
These progenitor cells and mature endothelial cells express several common molecular markers, such as von Willebrand factor, c-kit, Tie-2, Flt-1/VEGF-receptor-1, KDR/ Flk-1/VEGF receptor-2, Sca-1, CXCR4, CD146, CD31, and CD34 [13]. These results indicate that in SCF/c-kit signaling, both Akt and Erk1/2 have an essential role in capillary tube formation, whereas in VEGF/KDR signaling, Erk1/2 contributes much more dominantly than does Akt. it is well known that endothelial cells express c-kit, a receptor tyrosine kinase for SCF [20], the role of SCF/c-kit signaling in endothelial cells themselves has not been well understood to date [43].
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