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Molecular and Cellular Biology, July 2003, p. 4663-4672, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4663-4672.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Bcr Kinase Downregulates Ras Signaling by Phosphorylating AF-6 and Binding to Its PDZ Domain

G. Radziwill, R. A. Erdmann, U. Margelisch, and K. Moelling*

Institute of Medical Virology, University of Zurich, CH-8028 Zurich, Switzerland

Received 3 October 2002/ Returned for modification 21 November 2002/ Accepted 9 April 2003

The protein kinase Bcr is a negative regulator of cell proliferation and oncogenic transformation. We identified Bcr as a ligand for the PDZ domain of the cell junction and Ras-interacting protein AF-6. The Bcr kinase phosphorylates AF-6, which subsequently allows efficient binding of Bcr to AF-6, showing that the Bcr kinase is a regulator of the PDZ domain-ligand interaction. Bcr and AF-6 colocalize in epithelial cells at the plasma membrane. In addition, Bcr, AF-6, and Ras form a trimeric complex. Bcr increases the affinity of AF-6 to Ras, and a mutant of AF-6 that lacks a specific phosphorylation site for Bcr shows a reduced binding to Ras. Wild-type Bcr, but not Bcr mutants defective in binding to AF-6, interferes with the Ras-dependent stimulation of the Raf/MEK/ERK pathway. Since AF-6 binds to Bcr via its PDZ domain and to Ras via its Ras-binding domain, we propose that AF-6 functions as a scaffold-like protein that links Bcr and Ras to cellular junctions. We suggest that this trimeric complex is involved in downregulation of Ras-mediated signaling at sites of cell-cell contact to maintain cells in a nonproliferating state.

* Corresponding author. Mailing address: Institute of Medical Virology, University of Zurich, Gloriastr. 30, CH-8028 Zurich, Germany. Phone: 41 1 634 2652/53. Fax: 41 1 634 4967. E-mail: moelling{at}immv.unizh.ch.

Molecular and Cellular Biology, July 2003, p. 4663-4672, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4663-4672.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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