Major finding: The tyrosine phosphatase SHP2 determines whether parafibromin is a tumor suppressor or an oncogene.
Mechanism: Dephosphorylation of parafibromin promotes complex formation with β-catenin and Wnt signaling.
Impact: Findings provide insight into mechanisms of SHP-mediated neoplasms and developmental malformations.
SHP2 is a ubiquitously expressed protein tyrosine phosphatase encoded by the PTPN11 gene. Mutations in PTPN11 are associated with the hereditary developmental disorder Noonan syndrome in addition to adult and juvenile leukemia. SHP2 plays a central role in cell signaling events that promote growth and motility and is required for activation of the RAS signaling pathway. Deregulation of SHP also has been implicated in the development of multiple human malignancies. In a recent article, Takahashi and colleagues identified a unique role for SHP2 in the nucleus, as the determinant of the function of parafibromin/Cdc73, a component of the nuclear RNA polymerase II-associated factor (PAF) complex. Parafibromin has opposing functions that are context dependent. When complexed with the histone methyltransferase SUV39H1, parafibromin acts as a tumor suppressor that inhibits the transcription of cyclin D1 and c-myc. However, upon binding β-catenin, parafibromin switches to an oncogene that activates the promitogenic Wnt signaling pathway. The authors discovered that parafibromin is a unique substrate of SHP2 and that dephosphorylation by SHP2 determines its binding partner and therefore its nuclear function. In the absence of SHP2, parafibromin was tyrosine-phosphorylated and complexed with SUV39H1. Upon tyrosine dephosphorylation by SHP2, parafibromin preferentially bound to and trapped β-catenin in the nucleus. The formation and nuclear accumulation of the stable parafibromin/β-catenin complex was able to override parafibromin/SUV39H1-mediated repression and led to the induction of Wnt target genes. Overall, the important finding that SHP2 activity determines whether parafibromin behaves as a tumor suppressor or an oncogene offers mechanistic insight into how the deregulation of SHP2 may play a causative role in the development of neoplasms and developmental malformations.
Takahashi A, Tsutsumi R, Kikuchi I, Obuse C, Saito Y, Seidi A, et al. SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver. Mol Cell 2011;43:45–56.
Note: Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.