α2β1 integrin is one of the most important collagen-binding receptors and has been implicated in numerous widely spread thrombotic and immune diseases. α2β1 integrin is a potent tumour suppressor and its downregulation is associated with increased metastasis and poor prognosis in breast cancer. Currently, very little is known about the mechanism regulating α2β1 integrin cell surface expression and trafficking. Here, using a quantitative fluorescent microscopy-based RNAi assay, we investigated the impact of 386 cytoskeleton-associated or regulatory genes on α2-integrin endocytosis and scored 122 hits affecting α2-integrin intracellular accumulation. Of these, 83 were identified to be putative regulators of α2-integrin trafficking and/or expression with no observed effect on EGF or transferrin internalization. Further interrogation and validation of the siRNA screen revealed a role for KIF15, a microtubule-based molecular motor, as a significant inhibitor of α2-integrin endocytic trafficking. Our data suggest a novel role for KIF15 in mediating plasma membrane localization of the alternative clathrin adaptor Dab2, thus impinging on pathways regulating α2-integrin internalization.