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J. Biol. Chem., Vol. 277, Issue 2, 1002-1012, January 11, 2002
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From the The final step of the transduction pathway is the
activation of gene transcription, which is driven by kinase cascades
leading to changes in the activity of many transcription factors. Among these latter, PEA3/E1AF, ER81/ETV1, and ERM, members of the well conserved PEA3 group from the Ets family are involved in these processes. We show here that protein kinase A (PKA) increases the
transcriptional activity of human ERM and human ETV1, through a Ser
residue situated at the edge of the ETS DNA-binding domain. PKA
phosphorylation does not directly affect the ERM transactivation domains but does affect DNA binding activity. Unphosphorylated wild-type ERM bound DNA avidly, whereas after PKA phosphorylation it
did so very weakly. Interestingly, S367A mutation significantly reduced the ERM-mediated transcription in the presence of the kinase,
and the DNA binding of this mutant, although similar to that of
unphosphorylated wild-type protein, was insensitive to PKA treatment.
Mutations, which may mimic a phosphorylated serine, converted ERM from
an efficient DNA-binding protein to a poor DNA binding one, with
inefficiency of PKA phosphorylation. The present data clearly
demonstrate a close correlation between the capacity of PKA to increase
the transactivation of ERM and the drastic down-regulation of the
binding of the ETS domain to the targeted DNA. What we thus demonstrate
here is a relatively rare transcription activation mechanism through a
decrease in DNA binding, probably by the shift of a non-active form of
an Ets protein to a PKA-phosphorylated active one, which should be in a
conformation permitting a transactivation domain to be active.
ERM Transactivation Is Up-regulated by the Repression of DNA
Binding after the PKA Phosphorylation of a Consensus Site at the Edge
of the ETS Domain*
,§,§
UMR 8526 CNRS/Institut Pasteur de Lille,
Institut de Biologie de Lille, BP 447, 1 rue Calmette, 59021 Lille
Cedex, France and the ¶ Laboratoire de Virologie
Moléculaire, Faculté de Médecine,
Université Libre de Bruxelles, CP 614, 808 route de Lennik,
1070 Brussels, Belgium
*
This work was supported in part by the "Center National de
la Recherche Scientifique" (France), the "Institut Pasteur de
Lille," the "Association pour la Recherche contre le Cancer"
(France), and "Communauté Française" (Belgium) Grant
ARC 98/03-224.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.
To whom all correspondence should be addressed. Tel.:
33-320-87-11-26; Fax: 33-320-87-10-19; E-mail:
ylaunoit@ulb.ac.be.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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