Y. Ozawa et al., ANGIOTENSIN-II TYPE-1 RECEPTOR MEDIATES CELL-PROLIFERATION VIA PROTEIN-TYROSINE KINASE AND VOLTAGE-DEPENDENT CALCIUM CHANNELS, Biomedical research, 19(1), 1998, pp. 1-8
Here we examined the signaling pathway mediated by angiotensin II (Ang
II) type 1 receptor (AT(1)) leading to Ang II-induced proliferation o
f PC 12 cells stably expressing the recombinant AT(1) receptor (PC12/r
AT1). The cell number increased to 2.4-fold over the control 4 days af
ter Ang II addition. Ang II-induced [H-3]thymidine incorporation was a
ffected neither by pertussis toxin nor by calphostin C, a protein kina
se C (PKC) inhibitor. In contrast, the Ang II effect was almost comple
tely inhibited by the protein tyrosine kinase (PTK) inhibitor genistei
n. In addition, tyrphostin AG1478, an epidermal growth factor (EGF) re
ceptor-selective inhibitor, significantly inhibited Ang II-induced [H-
3]thymidine incorporation but had no effect on the basic fibroblast gr
owth factor action. Nicardipine, an L-type Ca2+ channel blocker, also
inhibited the Ang II function. Together, these data demonstrate that G
i proteins and PKC are not involved in Ang II-induced cell proliferati
on of PC12/rAT1 cells through the AT(1) receptor, and that Ca2+ influx
through voltage-dependent Ca2+ channels and activation of PTK(s) are
critical for this process. Furthermore, our data suggest that ligand-i
ndependent activation of a receptor tyrosine kinase(s), called transac
tivation, plays an important role in AT(1)-mediated cell proliferation
through Gq proteins.