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Identification of a novel activated form of the keratinocyte growth factor receptor by expression cloning from parathyroid adenoma tissue

Oncogene volume 18, pages 5497–5505 (1999)Cite this article

Abstract

Parathyroid adenomas are benign tumors in the parathyroid glands, whose pathogenesis is largely unknown. We utilized an expression cDNA cloning strategy to identify oncogenes activated in parathyroid adenomas. An expression cDNA library was prepared directly from a clinical sample of parathyroid adenoma tissue, transfected into NIH3T3 cells, and foci of morphologically transformed cells were isolated. Following plasmid rescue, we identified cDNAs for the keratinocyte growth factor receptor at a high frequency. Interestingly, approximately half of the clones encoded a variant receptor containing an altered C-terminus. Analysis of the transforming activity of the variant receptor revealed that the altered C-terminus up-regulated the transforming activity in a ligand-independent manner. The higher transforming activity was not accompanied by increase of dimerization or overall autophosphorylation of the receptor. However, tyrosine phosphorylation of downstream receptor substrates, including Shc isoforms and possibly FRS2, are increased in the transfectants expressing the parathyroid tumor-derived receptor. Genomic analysis showed that a previously unidentified exon was used to form the novel isoform. This alternative splicing appears to occur preferentially in parathyroid adenomas.

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Acknowledgements

We thank Drs JH Pierce and M Yanagishita for support; Drs GD Aurbach and M Chedid for tumor RNA samples; and Q Chen for technical assistance.

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Author notes

  1. Kazushige Sakaguchi

    Present address: Department of Molecular Medicine, Wakayama Medical College, 811-1 Kimiidera, Wakayama, 641-0012, Japan

  2. Matthew V Lorenzi

    Present address: Target Discovery Department, Zeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850-5437, Delaware, USA

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37 Room 1E24, 37 Convent Dr MSC 4255, Bethesda, MD 20892-4255, Maryland, USA

    Kazushige Sakaguchi, Matthew V Lorenzi & Toru Miki

  2. Glycobiology Program, National Institute of Dental Research, Bethesda, MD 20892, Maryland, USA

    Kazushige Sakaguchi

  3. Department of Pathology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105, Japan

    Hiroshi Matsushita

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  1. Kazushige Sakaguchi
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Sakaguchi, K., Lorenzi, M., Matsushita, H. et al. Identification of a novel activated form of the keratinocyte growth factor receptor by expression cloning from parathyroid adenoma tissue. Oncogene 18, 5497–5505 (1999). https://doi.org/10.1038/sj.onc.1202947

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