CKAP4 Regulates Cell Migration via the Interaction with and Recycling of Integrin

Cytoskeleton-associated protein 4 (CKAP4) is an endoplasmic reticulum protein that is also present in the cell surface membrane, where it acts as a receptor for Dickkopf1 (DKK1). In this study, we found that CKAP4 interacts with β1 integrin and controls the recycling of α5β1 integrin independently of DKK1. In S2-CP8 cells, knockdown of CKAP4 but not DKK1 enlarged the size of cell adhesion sites and enhanced cell adhesion to fibronectin, resulting in decreased cell migration. When CKAP4 was depleted, the levels of α5 but not β1 integrin were increased in the cell surface membrane. A similar phenotype was observed in other cells expressing low levels of DKK1. In S2-CP8 cells, α5 integrin was trafficked with β1 integrin and CKAP4 to the lysosome or recycled with β1 integrin. In CKAP4-depleted cells, the internalization of α5β1 integrin was unchanged, but its recycling was upregulated. Knockdown of sorting nexin 17 (SNX17), a mediator of integrin recycling, abrogated the increased α5 integrin levels caused by CKAP4 knockdown. CKAP4 bound to SNX17, and its knockdown enhanced the recruitment of α5β1 integrin to SNX17. These results suggest that CKAP4 suppresses the recycling of α5β1 integrin and coordinates cell adhesion sites and migration independently of DKK1.