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

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

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

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

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

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

^†This article is a `United States Government Work' paper as defined by the US Copyright Act.

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.

fibroblast growth factor receptor 2; alternative splicing; receptor tyrosine kinase; morphological transformation