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Signaling and Regulation

Phosphorylation of the Menin Tumor Suppressor Protein on Serine 543 and Serine 583

¹ Department of Medical Oncology, Dana-Farber Cancer Institute; ² Department of Pathology, Harvard Medical School, Boston, Massachusetts; and ³ The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts

Requests for reprints: Matthew Meyerson, Dana-Farber Cancer Institute, Department of Medical Oncology, 44 Binney St., Boston, MA 02115. Phone: 617-632-4768; Fax: 617-582-7880. E-mail: matthew_meyerson{at}dfci.harvard.edu

Multiple endocrine neoplasia type 1 (MEN-1) is a heritable syndrome typified by tumors in multiple endocrine organs, including the pituitary, parathyroids, and pancreatic islets. MEN-1 is attributable to mutations in the MEN1 tumor-suppressor gene that encodes the menin protein. Recent studies have implicated menin in transcriptional regulation and in covalent histone modification; however, little is known about modifications of the menin protein. Here, we report that menin is subject to phosphorylation on serine residues, including Ser⁵⁴³ and Ser⁵⁸³. Phosphorylation-defective mutants of either or both of these residues retain the associated histone methyltransferase activity of menin, as well as binding to the trithorax complex members Ash2L, Rbbp5, and MLL2 and to RNA polymerase II. Chromatin immunoprecipitation experiments reveal that binding of menin to the Hoxc8 locus is not affected by phosphorylation on Ser⁵⁴³ or Ser⁵⁸³. (Mol Cancer Res 2006;4(10):793–801)