Connexin Controls Cell-Cycle Exit and Cell Differentiation by Directly Promoting Cytosolic Localization and Degradation of E3 Ligase Skp2

Connexins and connexin channels play important roles in cell growth/differentiation and tumorigenesis. Here, we identified a relationship between a connexin molecule and a critical cell-cycle regulator. Our data show that connexin (Cx) 50 regulated lens cell-cycle progression and differentiation by modulating expression of cyclin-dependent kinase inhibitor p27/p57 and E3 ubiquitin ligase Skp2. Cx50 directly interacted with and retained Skp2 in the cytosol by masking the nuclear targeting domain of Skp2, and this effect was supported by an increased nuclear localization of Skp2, disruption of Skp2 interaction with importin-7, and decreased levels of p27/p57 in mouse lenses lacking Cx50. As a result, Cx50 increased auto-ubiquitination and subsequent degradation of Skp2. A mutation (V362E) on the C terminus of Cx50 disrupted the interaction between Cx50 and Skp2 and completely abolished such effects. Therefore, this study identifies a role for connexins in regulating cell-cycle modulators and, consequently, cell growth and differentiation. [Display omitted] •Connexin 50 governs cell-cycle existence and differentiation through p27/p57 and Skp2•Direct interaction with connexin 50 retains Skp2 in the cytosol•Connexin 50 promotes auto-ubiquitination and subsequent degradation of Skp2•p27/p57 protein is stabilized through downregulation of Skp2 Shi et al. examine junction/hemichannel-independent connexin function in governing cell growth and differentiation. They show that connexin 50 sequesters critical cell-cycle promoter and E3 ligase Skp2 in the cytosol. Connexin 50 promotes Skp2 degradation, resulting in stabilization of its substrate p27/p57 and thus the control of cell-cycle exit.