SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver.

Abstract

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.

• Authors: 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
• Journal: Molecular cell (Mol Cell) Vol. 43 Issue 1 Pg. 45-56 (Jul 08 2011) ISSN: 1097-4164 [Electronic] United States
• PMID: 21726809 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• CDC73 protein, human
• Proto-Oncogene Proteins c-myc
• Tumor Suppressor Proteins
• Wnt Proteins
• beta Catenin
• Cyclin D1
• Tyrosine
• Protein Tyrosine Phosphatase, Non-Receptor Type 11

Topics

• Animals
• COS Cells
• Cell Nucleus (metabolism)
• Chlorocebus aethiops
• Cyclin D1 (genetics, metabolism)
• Gene Expression Regulation
• HEK293 Cells
• Humans
• Mass Spectrometry
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (analysis, genetics, physiology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Signal Transduction
• Tumor Suppressor Proteins (genetics, metabolism, physiology)
• Tyrosine (metabolism)
• Wnt Proteins (metabolism)
• beta Catenin (metabolism)