The inositol polyphosphate 5-phosphatases selectively remove the phosphate from the 5-position of various phosphatidylinositols, which generate second messengers in response to extracellular signals. SKIP (skeletal muscle and kidney enriched inositol phosphatase) is a Type II 5-phosphatase that contains two highly conserved catalytic motifs. It is predominantly expressed in skeletal muscle, heart, brain, and kidney, but can also be detected in some tissues as a shorter protein, which is produced by alternative splicing. SKIP has a high affinity for phosphatidylinositol 4,5-bisphosphate as a substrate as well as inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, and phosphatidylinositol 3,4,5-trisphosphate. SKIP is localized in the cytoplasm and at ruffling membranes. Cells expressing SKIP display a loss of actin stress fibers where the protein was localized, suggesting that SKIP plays a negative role in regulating the actin cytoskeletal structure.