R-PTP-κ Inhibits Contact-Dependent Cell Growth by Suppressing E2F Activity

Density-dependent regulation of cell growth is presumed to be caused by cell-cell contact, but the underlying molecular mechanism is not yet clearly defined. Here, we report that receptor-type protein tyrosine phosphatase-kappa (R-PTP-kappa) is an important regulator of cell contact-dependent growth inhibition. R-PTP-kappa expression increased in proportion to cell density. siRNA-mediated R-PTP-kappa downregulation led to the loss of cell contact-mediated growth inhibition, whereas its upregulation reduced anchorage-independent cell growth in soft agar as well as tumor growth in nude mice. Expression profiling and luciferase reporter system-mediated signaling pathway analysis revealed that R-PTP-kappa induced under cell contact conditions distinctly suppressed E2F activity. Among the structural domains of R-PTP-kappa, the cytoplasmic domain containing the tandemly repeated PTP motif acts as a potent downregulator of the E2F pathway. Specifically, R-PTP-kappa suppressed CDK2 activity through the induction of p21Cip1/WAF-1 and p27Kip1, resulting in cell cycle arrest at the G1 phase. In transcriptome-based public datasets generated from four different tumor types, R-PTP-kappa expression was negatively correlated with the expression pattern and prognostic value of two known E2F1 target genes (CCNE1 and CDC25A). Therefore, our results indicate that the R-PTP-kappa-E2F axis plays a crucial role in cell growth-inhibitory signaling arising from cell-cell contact conditions.

Automated summary

Density-dependent regulation of cell growth is mediated by cell-cell contact, and R-PTP-kappa acts as a crucial regulator in this process by suppressing E2F activity and inducing cell cycle arrest.