Differential tyrosine phosphorylation status of the nuclear scaffold Parafibromin/CDC73 determines its role in cancer development.

Parafibromin/CDC73 is a multifunctional nuclear scaffold protein with context-dependent roles in tumorigenesis, functioning as both a tumor suppressor and an oncogenic driver. Originally identified as the product of the HRPT2 tumor suppressor gene, which is mutated in hyperparathyroidism-jaw tumor syndrome, Parafibromin represses the transcription of pro-mitogenic and oncogenic genes by interacting with SUV39H1. Parafibromin also associates with β-catenin, the central effector of the canonical Wnt (Wnt/β-catenin) pathway, a major morphogen signaling pathway frequently activated in cancer. The Parafibromin/β-catenin complex acts as a transcriptional co-activator, promoting pro-oncogenic Wnt targets such as c-Myc and Cyclin D1. This nuclear scaffold function of Parafibromin is regulated by its tyrosine phosphorylation status at Y290, Y293, and Y315: PTK6/BRK phosphorylates these tyrosine residues, whereas SHP2 dephosphorylates them. Dephosphorylated Parafibromin forms a stable complex with β-catenin, while phosphorylation prevents this interaction and abolishes Parafibromin-mediated Wnt activation. This mechanism may play a critical role in the development of hepatocellular carcinoma, in which SHP2-mediated tyrosine dephosphorylation of Parafibromin enhances Wnt signaling and promotes the dedifferentiation of hepatoma cells into cancer stem-like cells. In addition to β-catenin, Parafibromin acts as a multivalent scaffold that interacts with key transcriptional effectors in morphogen signaling pathways, such as Hedgehog and Notch signaling, as well as with YAP1 and TAZ in the mechanosensing Hippo signaling. Notably, these interactions of Parafibromin are also controlled by its phosphorylation status at Y290/Y293/Y315. Thus, deregulated Parafibromin tyrosine phosphorylation disrupts the coordinated intracellular signaling required for normal cell growth and differentiation, highlighting Parafibromin as a potential therapeutic target in cancer.