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Vol. 61, Issue 4, 817-831, April 2002
- and 
-Isoforms of the Human Thromboxane A2 Receptor
Department of Biochemistry, Conway Institute of Biomolecular and
Biomedical Research, University College Dublin, Dublin, Ireland
Thromboxane A2 (TXA2) stimulates mitogenic
growth of vascular smooth muscle. In humans, TXA2 signals
through two TXA2 receptor (TP) isoforms, termed TP
and
TP
. To investigate the mechanism of TXA2-mediated
mitogenesis, regulation of extracellular signal-regulated kinase (ERK)
signaling was examined in human embryonic kidney 293 cells
stably overexpressing the individual TP isoforms. The TXA2 mimetic 9,11-dideoxy-9,11-methano epoxy
prostaglandin F2
(U46619) elicited
concentration- and time-dependent activation of ERK1 and -2 through
both TPs with maximal TP- and TP-mediated ERK activation observed
after 10 and 5 min, respectively. U46619-mediated ERK activation was
inhibited by the TP antagonist
[1S-[1,2-(5Z)-3,4-]]-7-[3-[[2-(phenylamino)carbonyl]hydrazine] methyl]-7-oxabicyclo[-2,2,1-]hept-2yl]-5-heptenoic acid
(SQ29,548), and by the mitogen-activated protein kinase kinase
inhibitor 2'-amino-3'-methoxyflavone (PD 98059). Although ERK
activation through TP was dependent on
2-[1-(dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF 109203X)-sensitive protein kinase (PK) Cs, ERK activation through TP was only partially dependent on PKCs. ERK activation through both TP and TP was dependent on PKA and phosphoinositide 3-kinase (PI3K) class 1A, but not class 1B, and
was modulated by Harvey-Ras, A-Raf, c-Raf, and Rap1B/B-Raf and also
involved transactivation of the epidermal growth factor receptor.
Additionally, PKB/Akt was activated through TP and TP in a
PI3K-dependent manner. In conclusion, we have defined the key
components of TXA2-mediated ERK signaling and have
established that both TP and TP are involved. TXA2-mediated ERK activation through the TPs is a complex
event involving PKC-, PKA-, and PI3K-dependent mechanisms in addition to transactivation of the EGF receptor. TP and TP mediate ERK activation through similar mechanisms, although the time frame for
maximal ERK activation and PKC dependence differs.
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