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Molecular and Cellular Biology, November 2000, p. 8103-8111, Vol. 20, No. 21
Department of Cancer Medicine, Division of
Medicine, Imperial College School of Medicine, Hammersmith Campus,
London W12 ONN,1 and Department of
Molecular Pathology, Division of Basic Medical Sciences, Imperial
College School of Medicine, South Kensington Campus, London SW7
2AZ,2 United Kingdom
Received 1 June 2000/Returned for modification 5 July 2000/Accepted 27 July 2000
Members of the transforming growth factor
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Inactivation of Smad-Transforming Growth Factor
Signaling by Ca2+-Calmodulin-Dependent Protein Kinase
II

(TGF-
) family
transduce signals through Smad proteins. Smad signaling can be regulated by the Ras/Erk/mitogen-activated protein pathway in response
to receptor tyrosine kinase activation and the gamma interferon pathway
and also by the functional interaction of Smad2 with
Ca2+-calmodulin. Here we report that
Smad-TGF-
-dependent transcriptional responses are prevented
by expression of a constitutively activated Ca2+-calmodulin-dependent protein kinase II (Cam kinase
II). Smad2 is a target substrate for Cam kinase II in vitro at
serine-110, -240, and -260. Cam kinase II induces in vivo
phosphorylation of Smad2 and Smad4 and, to a lesser extent, Smad3.
A phosphopeptide antiserum raised against Smad2 phosphoserine-240
reacted with Smad2 in vivo when coexpressed with Cam kinase II and by
activation of the platelet-derived growth factor receptor, the
epidermal growth factor receptor, HER2 (c-erbB2), and the
TGF-
receptor. Furthermore, Cam kinase II blocked nuclear
accumulation of a Smad2 and induced Smad2-Smad4 hetero-oligomerization
independently of TGF-
receptor activation, while preventing
TGF-
-dependent Smad2-Smad3 interactions. These findings provide a
novel cross-talk mechanism by which Ca2+-dependent kinases
activated downstream of multiple growth factor receptors antagonize
cell responses to TGF-
.
*
Corresponding author. Present address: School of
Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United
Kingdom. Phone: 44-1603-593551. Fax: 44-1603-592250. E-mail:
a.chantry{at}uea.ac.uk.
Present address: Molecular Angiogenesis Laboratory, Imperial Cancer
Research Fund, Institute of Molecular Medicine, University of Oxford,
Oxford OX3 9DS, United Kingdom.
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