Atypical Mechanism of Regulation of the Wrch-1 Rho Family Small GTPase
| Autor: | Channing J. Der, Adam Shutes, Adrienne D. Cox, Anastacia C. Berzat |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
rho GTP-Binding Proteins
Blotting Western Fluorescence Polarization GTPase CDC42 Protein Serine-Threonine Kinases Biology General Biochemistry Genetics and Molecular Biology src Homology Domains Mice 03 medical and health sciences 0302 clinical medicine GTP-binding protein regulators Animals Humans Immunoprecipitation Small GTPase Pseudopodia Adaptor Proteins Signal Transducing DNA Primers GRB2 Adaptor Protein 030304 developmental biology 0303 health sciences Agricultural and Biological Sciences(all) Biochemistry Genetics and Molecular Biology(all) Kinase Signal transducing adaptor protein Protein Structure Tertiary 3. Good health Cell biology Gene Expression Regulation Biochemistry 030220 oncology & carcinogenesis NIH 3T3 Cells Guanine nucleotide exchange factor General Agricultural and Biological Sciences Plasmids Protein Binding Signal Transduction |
| Zdroj: | Current Biology. 14:2052-2056 |
| ISSN: | 0960-9822 |
| Popis: | Rho family GTPases are GDP/GTP-regulated molecular switches that regulate signaling pathways controlling diverse cellular processes [1, 2, 3]. Wrch-1 was identified as a Wnt-1 regulated Cdc42 homolog, upregulated by Wnt1 signaling in Wnt1-transformed mouse mammary cells [4], and was able to promote formation of filopodia and activate the PAK serine/threonine kinase. Wrch-1 shares significant sequence and functional similarity with the Cdc42 small GTPase. However, Wrch-1 possesses a unique N-terminal 46 amino acid sequence extension that contains putative Src homology 3 (SH3) domain-interacting motifs. We determined the contribution of the N terminus to Wrch-1 regulation and activity. We observed that Wrch-1 possesses properties that distinguish it from Cdc42 and other Rho family GTPases. Unlike Cdc42, Wrch-1 possesses an extremely rapid, intrinsic guanine nucleotide exchange activity. Although the N terminus did not influence GTPase or GDP/GTP cycling activity in vitro, N-terminal truncation of Wrch-1 enhanced its ability to interact with and activate PAK and to cause growth transformation. The N terminus associated with the Grb2 SH3 domain-containing adaptor protein, and this association increased the levels of active Wrch-1 in cells. We propose that Grb2 overcomes N-terminal negative regulation to promote Wrch-1 effector interaction. Thus, Wrch-1 exhibits an atypical model of regulation not seen in other Rho family GTPases. |
| Databáze: | OpenAIRE |
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