Schematic illustration of a hypothetical model of interactions of NHERF-2 in the ECs. In NHERF-2–silenced cells, loss of interaction with NHERF-2 inhibits PMCA localization and activation and increases free βCat. Thus, PMCA cannot pump calcium out, resulting in increased cytosolic Ca²⁺ that can induce c-Myc, which can then repress the p27 promoter and induce expression of cyclin D1. Cyclin D1 also sequesters and inhibits p27. Furthermore, c-Myc also induces expression of Cullin 1 and cyclin-dependent kinase subunit 1B, which are involved in p27 proteolysis. Free βCat also increases expression of cyclin D1 by binding to its promoter, all of which result in increased proliferation in NHERF-2–silenced cells.