PP2A‐B55 and its adapter proteins IER2 and IER5 regulate the activity of RB family proteins and the expression of cell cycle‐related genes

• Published in: The FEBS journal 2023-02, Vol.290 (3), p.745-762
• Main Authors: Doi, Kuriko, Takeuchi, Hiroto, Sakurai, Hiroshi
• Format: Article
• Language: English
• Subjects: Adapter proteins; Adapters; Adaptor proteins; Apoptosis; Cell cycle; Cell Cycle - genetics; Cell differentiation; Cell proliferation; Cyclin D1; Dephosphorylation; Derepression; E2F protein; E2F transcription factor; E2F Transcription Factors - metabolism; Gene expression; Genes; Growth factors; Immediate-Early Proteins - metabolism; Kinases; Phosphoprotein phosphatase; Phosphorylation; Protein phosphatase; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; protein phosphatase 2A; Protein Processing, Post-Translational; Proteins; RB protein; Retinoblastoma; Retinoblastoma protein; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Retinoblastoma-Like Protein p107 - genetics; Retinoblastoma-Like Protein p107 - metabolism; Transcription factors; Tumor suppressor genes; Tumors
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16612

The retinoblastoma (RB) tumour suppressor protein regulates cell proliferation, motility, differentiation and apoptosis. The phosphorylation state of RB is modulated by kinases and phosphatases, and RB exhibits phosphorylation‐sensitive interactions with E2F family transcription factors. Here, we characterize RB dephosphorylation by protein phosphatase 2A (PP2A). The growth factor‐inducible immediate early response (IER) proteins IER2 and IER5 possess an adapter‐like function in which IER proteins bind to both PP2A and its target proteins and enhance PP2A activity towards the proteins. IER2 interacts with RB and facilitates dephosphorylation of RB at T821/T826 by PP2A. In IER2 knockdown cells, elevated phosphorylation of RB resulted in reduced binding of RB to the promoters and derepression of cyclin D1 and p21. IER5 binds to both RB and RB‐like 1 (p107/RBL1), enhances dephosphorylation of these proteins by PP2A and represses the expression of various cell cycle‐related genes. However, IER2‐regulated dephosphorylation at T821/T826 is not necessary for the repression function of RB in cell mobility‐related gene expression. Our data identify PP2A adapter proteins as critical regulators of RB family proteins and suggest that the phosphorylation status of RB differentially affects gene expression. The immediate early response (IER) proteins IER2 and IER5 possess an adapter‐like function in which IER proteins bind to both PP2A and its target proteins and enhance PP2A activity towards the proteins. IER2 binds to tumour suppressor RB and facilitates dephosphorylation of RB at T821/T826 by PP2A. The PP2A–IER2 interactions enhance repressor functions of RB on cell cycle‐related gene expression.