Abstract
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-κ) is an important regulator of cell contact-dependent growth inhibition. R-PTP-κ expression increased in proportion to cell density. siRNA-mediated R-PTP-κ 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-κ induced under cell contact conditions distinctly suppressed E2F activity. Among the structural domains of R-PTP-κ, the cytoplasmic domain containing the tandemly repeated PTP motif acts as a potent downregulator of the E2F pathway. Specifically, R-PTP-κ 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-κ 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-κ-E2F axis plays a crucial role in cell growth-inhibitory signaling arising from cell-cell contact conditions.
Funder
Ministry of Science and ICT
the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, the Ministry of Health and Welfare
KRIBB Research Initiative Program
Subject
General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
Reference37 articles.
1. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. (2002). Molecular Biology of the Cell, Garland Science. [4th ed.].
2. Varied solutions to multicellularity: The biophysical and evolutionary consequences of diverse intercellular bonds;Day;Biophys. Rev.,2022
3. The hallmarks of cancer;Hanahan;Cell,2000
4. Keeping in touch with contact inhibition of locomotion;Mayor;Trends Cell Biol.,2010
5. Contact inhibition (of proliferation);McClatchey;Redux. Curr. Opin. Cell Biol.,2012
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