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

Atsushi Takahashi, Ryouhei Tsutsumi, Ippei Kikuchi, Chikashi Obuse, Yasuhiro Saito, Azadeh Seidi, Robert Karisch, Minerva Fernandez, Taewoo Cho, Naomi Ohnishi, Orit Rozenblatt-Rosen, Matthew Meyerson, Benjamin G. Neel, Masanori Hatakeyama

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)45-56
Number of pages12
JournalMolecular Cell
Issue number1
Publication statusPublished - 2011 Jul 8
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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