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J. Biol. Chem., Vol. 276, Issue 19, 16379-16390, May 11, 2001
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From the For the widely distributed P2Y
receptors for nucleotides, the transductional and functional responses
downstream of their coupling to G proteins are poorly characterized.
Here we describe apoptotic induction and the associated differential
stimulation of mitogen-activated protein (MAP) kinase family members by
the human P2Y1 receptor. The potent P2Y1
receptor agonist, 2-methylthio-ADP (2-MeSADP), stimulated the
extracellular-signal regulated kinases (ERK1/2) (EC50 ~5
nM) as well as several, but not all isoforms detected, of
the stress-activated protein kinase (SAPK) family. Phospho-isoforms of
p38 were unaffected. The induced kinase activity was blocked by the
P2Y1 receptor-selective antagonist,
adenosine-2'-phosphate-5'-phosphate, but unaffected by pertussis toxin.
In addition, the endogenous ligand ADP, and significantly also
2-MeSATP, induced concentration-dependent phosphorylation
changes in the same MAP kinase family members. The sustained activation
of ERK1/2 was associated with Elk-1 phosphorylation that was
abolished by the MEK1 inhibitor, PD 98059. However, the concomitant
transient activation of the SAPKs was not sufficient to induce c-Jun or
ATF-2 phosphorylation. The transient phase of the ERK activity was
partially inhibited either by the phosphatidylinositol 3-kinase
inhibitor, LY 294002, or the PKC inhibitor, Gö 6976. In addition,
the Src inhibitor, PP1, or expression of dominant negative Ras also
attenuated the transient phase of ERK phosphorylation. In contrast,
inhibition of Ras or Src had no effect on the sustained ERK
activity, which was critically dependent on phosphatidylinositol 3-kinase. The transient SAPK activity was suppressed by expression of a
dominant negative form of MKK4. Furthermore, this kinase-deficient mutant inhibited 2-MeSADP-induced caspase-3 stimulation and the associated decrease in cell number. In conclusion, adenosine di- and
triphosphate stimulation of the human P2Y1 receptor can
transiently activate the Ras-ERK cascade via the cooperative effects of
phosphatidylinositol 3-kinase, Src and PKC. The sustained ERK
stimulation, via a Ras-insensitive pathway, culminates in Elk-1
activation without inducing a proliferation effect. The transient SAPK
activity did not evoke transcription factor phosphorylation but was
required for the P2Y1 receptor-mediated apoptotic function.
Adenosine Nucleotides Acting at the Human P2Y1
Receptor Stimulate Mitogen-activated Protein Kinases and Induce
Apoptosis*
§,,,, and
Glaxo Institute of Applied Pharmacology,
Department of Pharmacology, University of Cambridge,
Cambridge CB2 1QJ and the ¶ 7TM Receptor Systems Unit, Molecular
Pharmacology Department, Glaxo Wellcome Medicines Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire
2G1 2NY, United Kingdom
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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