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Molecular and Cellular Biology, May 2004, p. 3769-3781, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.3769-3781.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Downstream-of-FGFR Is a Fibroblast Growth Factor-Specific Scaffolding Protein and Recruits Corkscrew upon Receptor Activation

Valérie Petit, Ute Nussbaumer, Caroline Dossenbach, and Markus Affolter*

Abteilung Zellbiologie, Biozentrum der Universität Basel, CH-4056 Basel, Switzerland

Received 21 October 2003/ Returned for modification 11 December 2003/ Accepted 3 February 2004

Fibroblast growth factor (FGF) receptor (FGFR) signaling controls the migration of glial, mesodermal, and tracheal cells in Drosophila melanogaster. Little is known about the molecular events linking receptor activation to cytoskeletal rearrangements during cell migration. We have performed a functional characterization of Downstream-of-FGFR (Dof), a putative adapter protein that acts specifically in FGFR signal transduction in Drosophila. By combining reverse genetic, cell culture, and biochemical approaches, we demonstrate that Dof is a specific substrate for the two Drosophila FGFRs. After defining a minimal Dof rescue protein, we identify two regions important for Dof function in mesodermal and tracheal cell migration. The N-terminal 484 amino acids are strictly required for the interaction of Dof with the FGFRs. Upon receptor activation, tyrosine residue 515 becomes phosphorylated and recruits the phosphatase Corkscrew (Csw). Csw recruitment represents an essential step in FGF-induced cell migration and in the activation of the Ras/MAPK pathway. However, our results also indicate that the activation of Ras is not sufficient to activate the migration machinery in tracheal and mesodermal cells. Additional proteins binding either to the FGFRs, to Dof, or to Csw appear to be crucial for a chemotactic response.

* Corresponding author. Mailing address: Abteilung Zellbiologie, Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Phone: 41 61 267 20 77. Fax: 41 61 267 20 78. E-mail: Markus.Affolter{at}unibas.ch.

Molecular and Cellular Biology, May 2004, p. 3769-3781, Vol. 24, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.9.3769-3781.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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