title: PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2.
abstract: Programmed death 1 (PD-1) is a potent inhibitor of T cell responses. PD-1 abrogates activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, but the mechanism remains unclear. We determined that during T cell receptor (TCR)/CD3- and CD28-mediated stimulation, PTEN is phosphorylated by casein kinase 2 (CK2) in the Ser380-Thr382-Thr383 cluster within the C-terminal regulatory domain, which stabilizes PTEN, resulting in increased protein abundance but suppressed PTEN phosphatase activity. PD-1 inhibited the stabilizing phosphorylation of the Ser380-Thr382-Thr383 cluster within the C-terminal domain of PTEN, thereby resulting in ubiquitin-dependent degradation and diminished abundance of PTEN protein but increased PTEN phosphatase activity. These effects on PTEN were secondary to PD-1-mediated inhibition of CK2 and were recapitulated by pharmacologic inhibition of CK2 during TCR/CD3- and CD28-mediated stimulation without PD-1. Furthermore, PD-1-mediated diminished abundance of PTEN was reversed by inhibition of ubiquitin-dependent proteasomal degradation. Our results identify CK2 as a new target of PD-1 and reveal an unexpected mechanism by which PD-1 decreases PTEN protein expression while increasing PTEN activity, thereby inhibiting the PI3K/Akt signaling axis.
authors.affiliation: Department of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Patsoukis
authors.forename: Lequn
authors.initials: L
authors.lastname: Li
authors.forename: Duygu
authors.initials: D
authors.lastname: Sari
authors.forename: Victoria
authors.initials: V
authors.lastname: Petkova
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Boussiotis
mesh_terms: D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004795:Enzyme Stability; D005786:Gene Expression Regulation; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D025801:Ubiquitin; D047390:Casein Kinase II; D051059:PTEN Phosphohydrolase