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Regulatory mechanisms pertaining to the self‐renewal of stem cells remain incompletely understood. Here, we show that functional interactions between small GTPase Rap1 and the adhesion molecule E‐cadherin uniquely regulate the self‐renewal of human embryonic stem cells (hESCs). Inhibition of Rap1 suppresses colony formation and self‐renewal of hESCs, whereas overexpression of Rap1 augments hESC clonogenicity. Rap1 does not directly influence the expression of the pluripotency genes Oct4 and Nanog. Instead, it affects the endocytic recycling pathway involved in the formation and maintenance of E‐cadherin‐mediated cell–cell cohesion, which is essential for the colony formation and self‐renewal of hESCs. Conversely, distinct from epithelial cells, disruption of E‐cadherin mediated cell–cell adhesions induces lysosome delivery and degradation of Rap1. This in turn leads to a further downregulation of E‐cadherin function and a subsequent reduction in hESC clonogenic capacity. These findings provide the first demonstration that the interplay between Rap1 and E‐cadherin along the endocytic recycling pathway serves as a timely and efficient mechanism to regulate hESC self‐renewal. Given the availability of specific activators for Rap1, this work provides a new perspective to enable better maintenance of human pluripotent stem cells. S TEM  C ELLS  2010;28:247–257

A Unique Interplay Between Rap1 and E‐Cadherin in the Endocytic Pathway Regulates Self‐Renewal of Human Embryonic Stem Cells