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Molecular and Cellular Biology, March 2008, p. 1802-1814, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.00201-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Atypical Rho GTPase Wrch1 Collaborates with the Nonreceptor Tyrosine Kinases Pyk2 and Src in Regulating Cytoskeletal Dynamics{triangledown}

Aino Ruusala and Pontus Aspenström*

Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden

Received 2 February 2007/ Returned for modification 27 July 2007/ Accepted 4 December 2007

The Cdc42-like GTPase Wnt responsive Cdc42 homolog 1 (Wrch1) has several atypical features; it has an N-terminal proline-rich extension that confers binding to SH3 domains, and it harbors an extremely high intrinsic nucleotide exchange activity, which overrides the normal GTPase activity. As a result, Wrch1 resides mainly in the active, GTP-loaded conformation under normal cellular conditions. We have previously shown that ectopic expression of Wrch1 in fibroblasts resulted in an altered cell morphology visible as a formation of filopodia, a loss of stress fibers, and a reduction in focal adhesions. Here, we show that Wrch1 binds to the nonreceptor tyrosine kinase Pyk2. The interaction required Wrch1 to be in a GTP conformation and also required an intact N-terminal proline-rich extension as well as an intact effector loop. Wrch1 requires Pyk2 in imposing the cytoskeletal effects, seen as the formation of filopodia, since treatment of cells with a Pyk2-specific small interfering RNA abrogated this response. Interestingly, we found that the presence and activity of Src were needed for the formation of a Wrch1-Pyk2 complex as well as for the Wrch1-induced formation of filopodia. We propose a model in which Pyk2 and Src function to coordinate the Wrch1-dependent effects on cytoskeletal dynamics.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden. Phone: 46 18 160408. Fax: 46 18 160420. E-mail: pontus.aspenstrom{at}licr.uu.se

{triangledown} Published ahead of print on 17 December 2007.

Molecular and Cellular Biology, March 2008, p. 1802-1814, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.00201-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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