A food-derived synergist of NGF signaling: identification of protein tyrosine phosphatase 1B as a key regulator of NGF receptor-initiated signal transduction.
Neurotrophins, such as the nerve growth factor (NGF), play an essential role in the growth, development, survival and functional maintenance of neurons in the central and peripheral systems. They also prevent neuronal cell death under various stressful conditions, such as ischemia and neurodegenerative disorders. NGF induces cell differentiation and neurite outgrowth by binding with and activating the NGF receptor tyrosine kinase followed by activation of a variety of signaling cascades. We have investigated the NGF-dependent neuritogenesis enhancer potential of a food-derived small molecule contained in Brassica vegetables and identified the protein tyrosine phosphatase (PTP) 1B as a key regulator of the NGF receptor-initiated signal transduction. Based on an extensive screening of Brassica vegetable extracts for the neuritogenic-promoting activity in the rat pheochromocytoma cell line PC12, we found the Japanese horseradish, wasabi (Wasabia japonica, syn. Eutrema wasabi), as the richest source and identified 6-methylsulfinylhexyl isothiocyanate (6-HITC), an analogue of sulforaphane isolated from broccoli, as one of the major neuritogenic enhancers in the wasabi. 6-HITC strongly enhanced the neurite outgrowth and neurofilament expression elicited by a low-concentration of NGF that alone was insufficient to induce neuronal differentiation. 6-HITC also facilitated the sustained-phosphorylation of the extracellular signal-regulated kinase and the autophosphorylation of the NGF receptor TrkA. It was found that PTP1B act as a phosphatase capable of dephosphorylating Tyr-490 of TrkA and was inactivated by 6-HITC in a redox-dependent manner. The identification of PTP1B as a regulator of NGF signaling may provide new clues about the chemoprotective potential of food components, such as isothiocyanates.
Shibata
Takahiro
T
Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
Nakahara
Hiroko
H
Kita
Narumi
N
Matsubara
Yui
Y
Han
Chunguang
C
Morimitsu
Yasujiro
Y
Iwamoto
Noriko
N
Kumagai
Yoshito
Y
Nishida
Motohiro
M
Kurose
Hitoshi
H
Aoki
Naohito
N
Ojika
Makoto
M
Uchida
Koji
K
D000818:Animals; D019921:Biotinylation / Q000379:methods; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017879:Isothiocyanates / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020917:Receptor, trkA / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
C111984:6-methylsulfinylhexyl isothiocyanate; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D016877:Oxidants; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D020932:Nerve Growth Factor; D006861:Hydrogen Peroxide; D020917:Receptor, trkA; D048052:Mitogen-Activated Protein Kinase 3; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D003545:Cysteine