Foxp3 Protein Stability Is Regulated by Cyclin-dependent Kinase 2*

Abstract

Background: Foxp3 post-translational regulation remains unclear. Results: Foxp3 is phosphorylated by cyclin-dependent kinase 2 (CDK2) and has increased stability and function without its CDK motifs. Conclusion: CDK2 is a negative regulator of Foxp3 function. Significance: Understanding how Foxp3 is stabilized could lead to new therapeutic measures for autoimmunity and transplantation.

PIM1 Kinase Phosphorylates the Human Transcription Factor FOXP3 at Serine 422 to Negatively Regulate Its Activity under Inflammation

“…Previous findings have shown that phosphorylation affects FOXP3 protein stability (11) and DNA binding activity (12). In this study, we unraveled a new mechanism by which human FOXP3 activity is regulated by PIM1.…”

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…70 For example, Foxp3 stability is regulated by Cdk2 through phosphorylation of 4 cyclin-dependent kinase motifs (Ser/Thr-Pro) within the Nterminal repressor domain, 71 and we have shown the capacity of IL-6 to suppress activation of Foxp3 expression by transforming growth factor b requires Cdk5-dependent phosphorylation of STAT3 on serine 727. 72 Moreover, we have also shown that Cdk5 controls IL-2 gene expression via repression of the mSin3a-histone deacetylase complex during T-cell activation.…”

Amphiregulin Confers Regulatory T Cell Suppressive Function and Tumor Invasion via the EGFR/GSK-3β/Foxp3 Axis

“…A recent study from Zhang et al (22) identified Ser 418 of the Foxp3 protein as a potential key phosphorylation site responsible for impaired Treg cell function in rheumatoid arthritis, which is dephosphorylated by PP1 in response to TNF-␣ signaling. Moreover, Morawski et al (40) reported that cyclin-dependent kinase 2 (CDK2) phosphorylates Foxp3 protein and alters its stability and activity and suggested that the cyclin-dependent kinase (CDK) motifs and nearby lysine residues cooperate to form a phosphodegron that regulates Foxp3 phosphorylation-dependent ubiquitination and degradation (22).…”