The interaction between KDR and interleukin-3 receptor (IL-3R) beta common modulates tumor neovascularization.
As vascular endothelial growth factor (VEGF), interleukin-3 (IL-3), released into the tumor microenvironment stimulates motogenic and mitogenic activity of normal and transformed cells. In the present study, we investigate the effects of IL-3 and VEGF on neoplastic vascular growth. Engagement of IL-3 receptor beta common (IL-3R beta c) contributes to both IL-3- and VEGF-induced Rac1 activation, cell migration and in vitro tube-like structure formation as shown by the expression of the dominant-negative IL-3R beta c construct (Delta455). In normal and transformed endothelial cells (EC) as well as in HEK 293 cells expressing KDR and IL-3R, VEGF and IL-3 treatment induces the formation of a KDR/IL-3R beta c complex. Moreover, as shown by the IL-3R Delta455 mutant or by the kinase dead KDR, functional receptors are required for this interaction. Consistent with the contribution of IL-3R beta c in both IL-3- and VEGF-mediated angiogenic signal, a reduced number of vessels inside tumors are found in mice injected with cells expressing the IL-3R Delta455 mutant. Thus, these findings provide a novel mechanism through which IL-3 and VEGF support cell survival and tumor neovascularization.
Dentelli
Patrizia
P
Department of Internal Medicine University of Torino, Corso Dogliotti 14, Torino 10126, Italy.
Rosso
Arturo
A
Garbarino
Giovanni
G
Calvi
Cristina
C
Lombard
Emanuela
E
Di Stefano
Paola
P
Defilippi
Paola
P
Pegoraro
Luigi
L
Brizzi
Maria Felice
MF
D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D047468:Immunoprecipitation; D007377:Interleukin-3 / Q000502:physiology; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic; D016185:Receptors, Interleukin-3 / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
D017931:DNA Primers; D007377:Interleukin-3; D016185:Receptors, Interleukin-3; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2