The formation of podosomes and invadopodia (actin-rich membrane protrusions involved in cell adhesion, migration and extracellular matrix remodelling) is upregulated by several oncogenic molecules, including members of the Src family of tyrosine kinases. On page 1726, Masato Okada and associates reveal new information on the molecular mechanisms that underlie podosome formation. By using an inducible system for Src activation, they show that the guanine nucleotide-exchange factor (GEF) for Rho family GTPases (Arhgef5) is necessary for Src-induced podosome formation. Furthermore, the authors show that Src-induced podosome formation is dependent on the Src SH3 domain, which binds to Arhgef5, and the Rho GTPases RhoA and Cdc42, which trigger rearrangements of the cytoskeleton that are necessary to generate podosomes. Arhgef5 is also tyrosine phosphorylated by Src, triggering a positive-feedback mechanism to upregulate Src activity. The Arhgef5 pleckstrin-homology domain (a phosphoinositide-interacting domain) is required for Arhgef5 targeting to podosomes and, interestingly, when Src...

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