Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Mol Cell. 2011 Jul 8;43(1):45-56. 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.
SHP2 的失调与恶性疾病以及发育障碍有关。尽管 SHP2 是 RAS 信号完全激活所必需的，但细胞生理学中的其他潜在作用尚未阐明。在这里，我们表明 SHP2 使 parafibromin/Cdc73 去磷酸化，后者是 RNA 聚合酶 II 相关因子 (PAF) 复合物的核心组成部分。已知 parafibromin 通过招募 SUV39H1 组蛋白甲基转移酶来抑制 cyclin D1 和 c-myc，从而作为肿瘤抑制因子发挥作用。然而，parafibromin 也可以通过结合 β-catenin 来发挥相反的作用，从而激活促进有丝分裂/致癌的 Wnt 信号。我们发现，在 SHP2 使酪氨酸去磷酸化后，parafibromin 获得了与 β-catenin 稳定结合的能力。parafibromin/β-catenin 相互作用会掩盖 parafibromin/SUV39H1 介导的转录抑制，并诱导包括 cyclin D1 和 c-myc 在内的 Wnt 靶基因的表达。因此，SHP2 控制 parafibromin 的相反功能，其失调可能导致肿瘤或发育畸形的发生。
