| Summary: | The Rho family GTPases are key signalling components that regulate the cytoskeleton and adhesion during cell migration. The Vav family of proteins act as guanine nucleotide exchange factors for several Rho GTPases. There are three isoforms of Vav expressed in mammalian cells: Vav1, the expression of which is largely restricted to haematopoietic cells, Vav2 and Vav3. In this study the role of Vav proteins in macrophage migration has been investigated using macrophages derived from mice lacking one or all three Vav isoforms. Cell migration and morphology were not significantly affected when single isoforms of Vav were absent from macrophages. However macrophages lacking all three isoforms adopted an elongated morphology in culture, which resulted in more persistent cell migration. Vav proteins were not required for chemotaxis to the macrophage chemo-attractant, colony-stimulating factor-1 (CSF-1). Vav proteins were also not required for CSF-1-stimulated Rac1 activation or Rac-mediated cytoskeletal reorganization in response to CSF-1. However, in response to CSF-1 stimulation Vav1 and Vav3 were phosphorylated on tyrosine residues, which has previously been shown to regulate their GEF catalytic activity. Macrophages lacking all three Vav proteins were defective in spreading upon adhesion to both glass and plastic. The defect correlated with reduced activation of Rac1 and RhoA, and a reduction in the activation of Erk1/2 and phosphorylation of paxillin in response to adhesion. Vav proteins are therefore not required for directed macrophage migration to the chemo-attractant CSF-1, but have an important role in adhesion-dependent signalling and are needed to maintain normal macrophage migration and morphology.
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