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Molecular and Cellular Biology, November 2000, p. 8103-8111, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Inactivation of Smad-Transforming Growth Factor beta  Signaling by Ca2+-Calmodulin-Dependent Protein Kinase II

Stephen J. Wicks,1 Stephen Lui,1,dagger Nadia Abdel-Wahab,2 Roger M. Mason,2 and Andrew Chantry1,*

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 beta  (TGF-beta ) 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-beta -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-beta receptor. Furthermore, Cam kinase II blocked nuclear accumulation of a Smad2 and induced Smad2-Smad4 hetero-oligomerization independently of TGF-beta receptor activation, while preventing TGF-beta -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-beta .

* 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.

dagger Present address: Molecular Angiogenesis Laboratory, Imperial Cancer Research Fund, Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom.

Molecular and Cellular Biology, November 2000, p. 8103-8111, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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