SHP2 Tyrosine Phosphatase Converts Parafibromin/Cdc73 from a Tumor Suppressor to an Oncogenic Driver

• Published in: Molecular cell Vol. 43; no. 1; pp. 45 - 56
• Main Authors: Takahashi, Atsushi, Tsutsumi, Ryouhei, Kikuchi, Ippei, Obuse, Chikashi, Saito, Yasuhiro, Seidi, Azadeh, Karisch, Robert, Fernandez, Minerva, Cho, Taewoo, Ohnishi, Naomi, Rozenblatt-Rosen, Orit, Meyerson, Matthew, Neel, Benjamin G., Hatakeyama, Masanori
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.07.2011
• Subjects: abnormal development; Animals; beta Catenin - metabolism; Cell Nucleus - metabolism; cell physiology; Cercopithecus aethiops; COS Cells; Cyclin D1 - genetics; Cyclin D1 - metabolism; cyclins; dephosphorylation; DNA-directed RNA polymerase; Gene Expression Regulation; genes; HEK293 Cells; histones; Humans; malformations; Mass Spectrometry; methyltransferases; Mice; Mice, Inbred C57BL; neoplasms; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - analysis; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - physiology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA; Signal Transduction; signals; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - physiology; tyrosine; Tyrosine - metabolism; Wnt Proteins - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.05.014

Deregulation of SHP2 is associated with malignant diseases as well as developmental disorders. Although SHP2 is required for full activation of RAS signaling, other potential roles in cell physiology have not been elucidated. Here we show that SHP2 dephosphorylates parafibromin/Cdc73, a core component of the RNA polymerase II-associated factor (PAF) complex. Parafibromin is known to act as a tumor suppressor that inhibits cyclin D1 and c-myc by recruiting SUV39H1 histone methyltransferase. However, parafibromin can also act in the opposing direction by binding β-catenin, thereby activating promitogenic/oncogenic Wnt signaling. We found that, on tyrosine dephosphorylation by SHP2, parafibromin acquires the ability to stably bind β-catenin. The parafibromin/β-catenin interaction overrides parafibromin/SUV39H1-mediated transrepression and induces expression of Wnt target genes, including cyclin D1 and c-myc. Hence, SHP2 governs the opposing functions of parafibromin, deregulation of which may cause the development of tumors or developmental malformations. [Display omitted] ► SHP2 tyrosine-dephosphorylates parafibromin/Cdc73, a putative tumor suppressor ► On dephosphorylation, parafibromin acquires the ability to bind β-catenin ► SHP2 stimulates Wnt signaling by promoting parafibromin/β-catenin interaction ► Binding to β-catenin overrides the tumor-suppressive functions of parafibromin