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SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver
- Source :
- Molecular cell. 43(1)
- Publication Year :
- 2010
-
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 pro-mitogenic/oncogenic Wnt signaling. We found that, upon 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.
- Subjects :
- Beta-catenin
Parafibromin
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein tyrosine phosphatase
Mass Spectrometry
Article
Proto-Oncogene Proteins c-myc
Mice
Cyclin D1
Chlorocebus aethiops
Animals
Humans
Phosphorylation
Molecular Biology
beta Catenin
Transrepression
Genetics
Cell Nucleus
biology
Tumor Suppressor Proteins
Wnt signaling pathway
Cell Biology
Cell biology
Mice, Inbred C57BL
Wnt Proteins
HEK293 Cells
Gene Expression Regulation
Histone methyltransferase
COS Cells
biology.protein
Tyrosine
Signal Transduction
Subjects
Details
- ISSN :
- 10974164
- Volume :
- 43
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Molecular cell
- Accession number :
- edsair.doi.dedup.....345e28ff8d20da20d2a252dbb7e64b15