When PIPKIγ (green, left) is no longer present (right), E-cadherin (red) is stuck in the cytoplasm.

The protein E-cadherin puts a leash on cancer cells, and on page 343 Ling et al. clarify how cells deliver the molecule to the membrane. A connector protein fastens E-cadherin to a transporter that hauls it to the cell surface. The findings might improve researchers' understanding of metastasis in epithelial cancers and reveal how cells direct E-cadherin to the basolateral portion of the membrane.

Epithelial cells hold tight to their neighbors through connections called adherens junctions. The structures form when E-cadherin proteins protruding from adjoining cells clasp, and the cells snuggle up. To control these liaisons, cells add E-cadherin to the membrane or withdraw it into the cytoplasm. Because E-cadherin blocks cancer cells from spreading, researchers want to determine how cells direct the protein to the membrane.

Ling et al. observed that the protein PIPKIγ concentrates at adherens junctions, so they investigated whether the molecule takes part in transporting E-cadherin. They first determined that PIPKIγ latches onto E-cadherin. In cells depleted of PIPKIγ by RNAi, E-cadherin no longer made it to the cell membrane and accumulated in the cytoplasm.

Its partners in E-cadherin transport, the researchers discovered, include the clathrin adaptor protein complexes, which cart proteins to and from the membrane. If cells manufacture a faulty version of one adaptor protein that lacks the PIPKIγ binding site, little E-cadherin makes it to the membrane, the scientists found. They conclude that proteins can reach the cell membrane either by binding to clathrin adaptors directly, as shown before, or by binding PIPKIγ, which in turn links to the adaptors.

The results could clarify the defect behind a type of inherited stomach cancer. Patients carry a mutation that alters the site where E-cadherin couples to PIPKIγ. The two molecules bind weakly, and E-cadherin stays in the cytoplasm. The findings also indicate that PIPKIγ helps target E-cadherin to the basolateral membrane, but the possible mechanism or involvement of signaling pathways is not yet clear.