title: Critical role of WW domain phosphorylation in regulating phosphoserine binding activity and Pin1 function.
abstract: Phosphoserine-binding modules help determine the specificity of signal transduction events. One such module, the group IV WW domain, plays an essential role in targeting the phosphorylation-specific prolyl isomerase Pin1 to its substrates. These modules require Ser/Thr phosphorylation of their ligands for binding activity. However, phosphorylation of these modules and its functional significance have not been described, nor is it known whether the function of Pin1 is regulated. Here we show that Pin1 WW domain is phosphorylated on Ser(16) both in vitro and in vivo. Further, this phosphorylation regulates the ability of the WW domain to mediate Pin1 substrate interaction and cellular localization. Moreover, both Pin1 and WW domain mutants refractory to Ser(16) phosphorylation act as dominant-negative mutants to induce mitotic block and apoptosis and increase multinucleated cells with 8 N DNA content. Thus, phosphorylation is a new mechanism critical for regulating WW domain phosphoserine binding activity and Pin1 function.
authors.affiliation: Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.forename: Yih-Cherng
authors.initials: YC
authors.lastname: Liou
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Noel
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
mesh_terms: D002453:Cell Cycle; D004247:DNA / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000502:physiology*; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D013997:Time Factors
chemical_list: D008164:Luminescent Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D010768:Phosphoserine; D013912:Threonine; D012694:Serine; D004247:DNA; D005982:Glutathione Transferase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase