TY - JOUR
T1 - SHP2 Tyrosine Phosphatase Converts Parafibromin/Cdc73 from a Tumor Suppressor to an Oncogenic Driver
AU - Takahashi, Atsushi
AU - Tsutsumi, Ryouhei
AU - Kikuchi, Ippei
AU - Obuse, Chikashi
AU - Saito, Yasuhiro
AU - Seidi, Azadeh
AU - Karisch, Robert
AU - Fernandez, Minerva
AU - Cho, Taewoo
AU - Ohnishi, Naomi
AU - Rozenblatt-Rosen, Orit
AU - Meyerson, Matthew
AU - Neel, Benjamin G.
AU - Hatakeyama, Masanori
N1 - Funding Information:
We thank Robert A. Weinberg for valuable discussions and comments. We also thank Akira Kikuchi, Mineo Kurokawa, Mitsuyasu Kato, Shinya Tanaka, and Yusuke Ohba for providing plasmids. We also thank Akiko Yano for help. This work was supported by Grants-in-Aid for the Scientific Research on Innovative Area from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (M.H.), by R37CA39152 (B.G.N.), and by the Princess Margaret Hospital Foundation and Ontario Ministry of Health and Long-Term Care. R.K. is the recipient of a graduate fellowship from the Canadian Institutes for Health Research.
PY - 2011/7/8
Y1 - 2011/7/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2011.05.014
DO - 10.1016/j.molcel.2011.05.014
M3 - Article
C2 - 21726809
AN - SCOPUS:79959861920
VL - 43
SP - 45
EP - 56
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 1
ER -