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Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors

Oncogene volume 27, pages 3508–3515 (2008)Cite this article

Abstract

SHP-2 protein tyrosine phosphatase plays an important role in activation of the RAS-dependent signaling. Gain-of-function mutations in the PTPN11 gene, which encodes SHP-2, have been found in the leukemia-prone developmental disorder Noonan syndrome as well as sporadic childhood leukemias, indicating that SHP-2 is a bona fide human oncoprotein. However, the role of SHP-2 mutations in non-hematological malignancies remains obscure. Here, we screened for PTPN11 mutations in primary solid tumors and identified a 1520C>A mutation that causes threonine-507 to lysine (T507K) substitution in the phosphatase domain of SHP-2 in a case of hepatocellular carcinoma. T507K SHP-2 exhibited altered substrate specificity with slightly elevated basal phosphatase activity. Upon expression in NIH3T3 cells, T507K SHP-2 induced transformed foci, which was not observed with wild type, Noonan-specific or leukemia-specific SHP-2. Furthermore, NIH3T3 cells transformed by T507K SHP-2 showed anchorage-independent growth and developed tumors in nude mice. These results indicate that quantitative and/or qualitative alteration in phosphatase activity determines the transforming potential as well as target cell/tissue spectrum of individual SHP-2 mutants as oncoproteins. Although rare in solid tumors, the identified T507K SHP-2 represents a distinct class of SHP-2 mutants with oncogenic RAS-like transforming activity, which could contribute to the development of solid tumors.

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Acknowledgements

We thank many physicians who cared for patients at the affiliated hospitals of the Division of Surgical Oncology, Graduate School of Medicine, Hokkaido University. We also thank Drs Miyuki Kida, Ryouhei Tsutsumi and Naoko Murata-Kamiya for technical support and valuable discussion. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and by a research grant from Takeda Science Foundation (MH).

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Authors and Affiliations

  1. Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    D Miyamoto, A Takahashi, Y Yomogita, H Higashi & M Hatakeyama

  2. Division of Surgical Oncology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    D Miyamoto, M Miyamoto & S Kondo

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  1. D Miyamoto
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  2. M Miyamoto
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Correspondence to M Hatakeyama.

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Miyamoto, D., Miyamoto, M., Takahashi, A. et al. Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors. Oncogene 27, 3508–3515 (2008). https://doi.org/10.1038/sj.onc.1211019

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