NDLI: Usage of Tautomycetin, a Novel Inhibitor of Protein Phosphatase 1 (PP1), Reveals That PP1 Is a Positive Regulator of Raf-1 in Vivo

Content Provider	Journal of Biological Chemistry (JBC)
Author	Mitsuhashi, Shinya Shima, Hiroshi Tanuma, Nobuhiro Matsuura, Nobuyasu Takekawa, Mutsuhiro Urano, Takeshi Kataoka, Tohru Ubukata, Makoto Kikuchi, Kunimi
Abstract	Protein phosphatase type 1 (PP1), together with protein phosphatase 2A (PP2A), is a major eukaryotic serine/threonine protein phosphatase involved in regulation of numerous cell functions. Although the roles of PP2A have been studied extensively using okadaic acid, a well known inhibitor of PP2A, biological analysis of PP1 has remained restricted because of lack of a specific inhibitor. Recently we reported that tautomycetin (TC) is a highly specific inhibitor of PP1. To elucidate the biological effects of TC, we demonstrated in preliminary experiments that treatment of COS-7 cells with 5 μm TC for 5 h inhibits endogenous PP1 by more than 90% without affecting PP2A activity. Therefore, using TC as a specific PP1 inhibitor, the biological effect of PP1 on MAPK signaling was examined. First, we found that inhibition of PP1 in COS-7 cells by TC specifically suppresses activation of ERK, among three MAPK kinases (ERK, JNK, and p38). TC-mediated inhibition of PP1 also suppressed activation of Raf-1, resulting in the inactivation of the MEK-ERK pathway. To examine the role of PP1 in regulation of Raf-1, we overexpressed the PP1 catalytic subunit (PP1C) in COS-7 cells and found that PP1C enhanced activation of Raf-1 activity, whereas phosphatase-dead PP1C blocked Raf-1 activation. Furthermore, a physical interaction between PP1C and Raf-1 was also observed. These data strongly suggest that PP1 positively regulates Raf-1 in vivo.
Related Links	http://www.jbc.org/content/278/1/82.abstract
Ending Page	88
Starting Page	82
Page Count	7
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	1
Volume Number	278
DOI	10.1074/jbc.M208888200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2003-01-03
Access Restriction	Open
Subject Keyword	Serine/threonine protein phosphatase type 1 (PP1) Serine/threonine protein phosphatase type 2A (PP2A) Serine/threonine protein phosphatase type 2B (PP2B) Serine/threonine protein phosphatase (PP) Okadaic acid (OA) Tautomycetin (TC) Mitogen-activated protein kinase (MAPK) PP1 catalytic subunit (PP1C) Tautomycin (TM) Extracellular signal-regulated kinase (ERK) MAPK/ERK kinase (MEK) C-Jun NH2 kinase (JNK) Homologue of the budding yeast HOG1 protein (p38) Dimethyl sulfoxide (Me2SO) Epidermal growth factor (EGF) GlutathioneS-transferase (GST) Protein phosphatase inhibitor-2 (I-2) 12-O-tetradecanoyl-13-phorbol acetate (TPA) Hemagglutinin (HA) MECHANISMS OF SIGNAL TRANSDUCTION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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