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Annals of Clinical & Laboratory Science 33:200-207 (2003)
© 2003 Association of Clinical Scientists

A Protein Methyl Transferase, PRMT5, Selectively Blocks Oncogenic ras-p21 Mitogenic Signal Transduction

Lyndon Chie1,2, Jeffry R. Cook3, Denise Chung2, Ralf Hoffmann3, Zhihong Yang3, Youngsun Kim3, Sidney Pestka3 and Matthew R. Pincus1,4
1 Department of Pathology & Laboratory Medicine, New York Harbor VA Medical Center, Brooklyn, NY
2 Departments of Biology & Chemistry, Long Island University, Brooklyn, NY
3 Department of Molecular Genetics & Microbiology, R. W. Johnson Medical Center, Piscataway, NJ
4 Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY

Address correspondence to (a) Dr Matthew R. Pincus,VA Medical Center, 800 Poly Place, Brooklyn, NY 11209; tel 718 630 3688; e-mail matthew.pincus2{at}med.va.gov, or to (b) Dr Sidney Pestka, RW Johnson Medical Center, 675 Hoes Lane, Piscataway, NJ; tel 732 235 4567; e-mail pestka{at}waksman.rutgers.edu.

A Janus-2 (JAK-2) binding protein, JBP1, has been found to function as an arginine methyl transferase and is now designated PRMT5. Co-injection of plasmids encoding this protein together with oncogenic (Val 12-containing) ras-p21 protein into Xenopus laevis oocytes results in strong inhibition of oncogenic p21-induced oocyte maturation. This inhibition appears to be dependent on the methyl transferase function since a partially active R368A mutant shows diminished ability to inhibit Val 12-p21-induced oocyte maturation, and an almost totally inactive GAGRG (365–369) deletion mutant fails to inhibit Val 12-p21-induced maturation. In contrast, PRMT5 (JBP1) does not inhibit insulin-induced oocyte maturation. Since insulin-induced maturation depends on activation of cellular ras-p21, PRMT5 does not appear to inhibit the wild-type p21 protein. We also find that arginine methyl transferase inhibitors strongly block oncogenic ras-p21-activated, but not insulin-activated, wild-type ras-p21-induced oocyte maturation. Thus signaling by oncogenic p21 appears to involve methyltransferases uniquely. Surprisingly, the active site peptide, Gly-Arg-Gly, strongly suppresses insulin-induced maturation but has no effect on Val 12-p21-induced maturation. This peptide may therefore be useful in defining steps in the wild-type ras pathway.

Keywords: JAK-2-binding protein, protein arginine methyltrasferase (PRMT5), oncogenic ras-p21, insulin




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