Dock8 was identified during a yeast two hybrid (YTH) screen for proteins that interact with the Rho family small G protein Cdc42.Subsequent northern blot analysis revealed high levels of Dock8 expression in the placenta, lung, kidney and pancreas as well as lower levels in the heart, brain and skeletal muscle.

Dock8 shares the same core domain arrangement as all other DOCK proteins, with a DHR2 domain which, in other proteins, contains GEF activity and a DHR1 domain known, in other proteins, to interact with phospholipids. In the YTH system Dock8 was reported to interact with both Rac1 and Cdc42. However, no stable interaction between Dock8 and these small G proteins was observed in a GST-pulldown assay.