The homing ability of hematopoietic stern cells (HSCs) was a critical step for transplantation and subsequent hematopoiesis. Although the HSC transplantation was widely used for many diseases, the mechanism by which HSC homing was regulated remained poorly understood. F-box protein S-phase kinase associated protein2 (Skp2), a component of the Skp2-SCF E3 ligase complex, was regarded as a cell cycle regulator by controlling the level of p21 and p27 through ubiquitination. We recently reported an important role of Skp2 in maintaining HSC pool size, quiescent stage and self-renewal ability. In this current study, we showed that Skp2 was a novel and critical regulator for maintaining the homing of HSCs as well as their residence in the endosteal niche. Microarray analysis together with biochemical validations revealed that Skp2 deficiency profoundly reduced the expression of beta-catenin and its target genes. Knockdown of beta-catenin mimicked the decline of HSC homing upon Skp2 deficiency, suggesting that Skp2 may regulate beta-catenin and its target gene expression to orchestrate HSC homing. Our study not only identified Skp2 as a new regulator for maintaining beta-catenin expression and HSC homing, but also suggested that Skp2 may serve as a predictive marker for monitoring the transplantation efficiency. (c) 2014 Elsevier Inc. All rights reserved.