BACKGROUND: The Mn(2+)/Mg(2+)-dependent Ser/Thr phosphatase PPM1F was identified to control integrin activity. Furthermore, PPM1F regulates several protein kinases known to be involved in organizing the cytoskeleton and other cellular functions. Therefore, PPM1F appears critical for a multitude of physiological processes. RESULTS: Here, we report the phenotype of ppm1f gene disruption in mice. While heterozygous ppm1f ± mice are viable and fertile, ppm1f-/- mice show severe defects and significant morphological abnormalities in the developing brain and vasculature and abort embryonic development at day E10.5. Isolated ppm1f-/- MEFs or PPM1F-depleted human neuro-epithelial cells display enhanced integrin-dependent cell adhesion, deregulated PAK phosphorylation, and perturbed cell migration. These phenotypes were reversed by re-expression of the wildtype enzyme, but not the phosphatase-inactive PPM1F. In different human tumor cell types, PPM1F expression levels directly correlated with invasive potential, while deletion of PPM1F abrogates tissue invasion. CONCLUSIONS: These results highlight the non-redundant role of this enzyme in integrin and PAK regulation and identify PPM1F as a promising target to limit tumor metastasis.