Mol. Biol. Cell 11 (1): 93-101

Copyright © 2000 by The American Society for Cell Biology.

Vol. 11, Issue 1, 93-101, January 2000

Ultraviolet Light Induces Redox Reaction-mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

Masashi Kato,^* Toshihide Iwashita, Kozue Takeda,^* Anwarul A. Akhand,^* Wei Liu,^* Motoi Yoshihara,^* Naoya Asai, Haruhiko Suzuki,^* Masahide Takahashi, and Izumi Nakashima^*

Departments of  ^*Immunology and  Pathology, Nagoya University School of Medicine, Nagoya, Aichi 466-8550, Japan

The c-RET proto-oncogene encodes a receptor-type tyrosine kinase, and its mutations in the germ line are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B). Ret kinases are constitutively activated as a result of MEN2A mutations (Ret-MEN2A) or MEN2B mutations (Ret-MEN2B). Here we demonstrate that UV light (UV) irradiation induces superactivation of the constitutively activated Ret-MEN2A and Ret-MEN2B as well as activation of c-Ret. Before UV irradiation, small percentages of c-Ret (3-4%) and Ret-MEN2B (1-2%) and large percentages of Ret-MEN2A (30-40%) were dimerized through disulfide bonds. These dimerized Ret proteins were preferentially autophosphorylated, suggesting a close relation between up-regulated kinase activity and disulfide bond-mediated dimerization of Ret proteins. We found that UV irradiation promotes the disulfide bond-mediated dimerization of the Ret proteins, in close association with activation and superactivation of Ret kinases. UV irradiation also induced dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Interestingly, the levels of basic kinase activity and dimerization of Ret-PTC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-PTC-1 was replaced by alanine, were low and were not increased by UV irradiation. These results suggest that Ret-PTC-1 cysteine 376 is one of possibly multiple critical target amino acids of UV for Ret kinase activation. Overexpression of Cu/Zn superoxide dismutase in cells as a result of gene transfection prevented both the UV-mediated promotion of dimerization and the superactivation of Ret-MEN2A kinase. These results suggest that the UV-induced free radicals in cells attack intracellular domains of Ret to dimerize the kinase proteins for superactivation.

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Corresponding author. E-mail address: inakashi{at}tsuru.med.nagoya-u.ac.jp.

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Molecular Biology of the Cell
Vol. 11, 93-101, January 2000
Copyright © 2000 by The American Society for Cell Biology

Ligand Binding Rapidly Induces Disulfide-dependent Dimerization of Glycoprotein VI on the Platelet Plasma Membrane.

J. F. Arthur, Y. Shen, M. L. Kahn, M. C. Berndt, R. K. Andrews, and E. E. Gardiner (2007)
J. Biol. Chem. 282, 30434-30441
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Fer-Mediated Cortactin Phosphorylation Is Associated with Efficient Fibroblast Migration and Is Dependent on Reactive Oxygen Species Generation during Integrin-Mediated Cell Adhesion.

W. Sangrar, Y. Gao, M. Scott, P. Truesdell, and P. A. Greer (2007)
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E. Giannoni, F. Buricchi, G. Raugei, G. Ramponi, and P. Chiarugi (2005)
Mol. Cell. Biol. 25, 6391-6403
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Interdependent Regulation of Insulin Receptor Kinase Activity by ADP and Hydrogen Peroxide.

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Identification of RET Autophosphorylation Sites by Mass Spectrometry.

Y. Kawamoto, K. Takeda, Y. Okuno, Y. Yamakawa, Y. Ito, R. Taguchi, M. Kato, H. Suzuki, M. Takahashi, and I. Nakashima (2004)
J. Biol. Chem. 279, 14213-14224
 |  Abstract »  |  Full Text »  |  PDF »

Genomic Variation in Multigenic Traits: Hirschsprung Disease.

A.S. MCCALLION, E.S. EMISON, C.S. KASHUK, R.T. BUSH, M. KENTON, M.M. CARRASQUILLO, K.W. JONES, G.C. KENNEDY, M.E. PORTNOY, E.D. GREEN, et al. (2003)
Cold Spring Harb Symp Quant Biol 68, 373-382
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Repair by Src Kinase of Function-impaired RET with Multiple Endocrine Neoplasia Type 2A Mutation with Substitutions of Tyrosines in the COOH-Terminal Kinase Domain for Phenylalanine.

M. Kato, K. Takeda, Y. Kawamoto, T. Iwashita, A. A. Akhand, T. Senga, M. Yamamoto, G. Sobue, M. Hamaguchi, M. Takahashi, et al. (2002)
Cancer Res. 62, 2414-2422
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