A protein methyl transferase, PRMT5, selectively blocks oncogenic ras-p21 mitogenic signal transduction.
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 leavis 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.
Chie
Lyndon
L
Department of Pathology & Laboratory Medicine, New York Harbor VA Medical Center, Brooklyn, NY 11209, USA.
Cook
Jeffry R
JR
Chung
Denise
D
Hoffmann
Ralf
R
Yang
Zhihong
Z
Kim
Youngsun
Y
Pestka
Sidney
S
Pincus
Matthew R
MR
D000818:Animals; D005260:Female; D007328:Insulin / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D011496:Protein Methyltransferases / Q000494:pharmacology*; D011484:Protein-Arginine N-Methyltransferases; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014982:Xenopus laevis
D007328:Insulin; D008934:Mitogens; D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D016283:Proto-Oncogene Proteins p21(ras)