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Submitted on April 29, 2004
Accepted on June 22, 2004
Departments of Medicine, Laboratory Medicine and Pathobiology, University of Toronto, The Freeman Centre for Endocrine Oncology, Mount Sinai Hospital, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G-1X5
* To whom correspondence should be addressed. E-mail: sylvia.asa{at}uhn.on.ca.
We previously identified pituitary tumor-derived FGFR4 (ptd-FGFR4), an alternatively transcribed N-terminally truncated cytoplasmic receptor isoform. Unlike wild-type FGFR4, ptd-FGFR4 facilitates cell transformation and results in pituitary tumor formation in transgenic mice. To investigate differences in the tumorigenic properties of FGFR4 and ptd-FGFR4, we examined their abilities to modulate cell adhesiveness. Introduction of ptd-FGFR4 into GH4 pituitary cells or NIH 3T3 fibroblasts resulted in significant reduction in cell adhesion to a collagen IV matrix compared with FGFR4- or empty vector-transfected cells. This adhesive difference was evident in the absence or presence of FGF stimulation. Furthermore, treatment with 
1-integrin neutralizing antibody markedly reduced adhesiveness in FGFR4-transfected cells but had little effect on the depressed adhesiveness of ptd-FGFR4-transfected cells. Unlike wild-type FGFR4, ptd-FGFR4 does not associate with NCAM. Cells expressing FGFR4 demonstrate membranous N-cadherin with a non-invasive growth pattern identical to control GH4 cells when injected into immunodeficient mice. In contrast, ptd-FGFR4-expressing cells develop invasive tumors in vivo with marked loss of N-cadherin that localizes to the cytoplasm. Consistent with these changes, -catenin expression was diminished and its interaction with N-cadherin disrupted in the presence of ptd-FGFR4 but both were intact in the presence of wild-type FGFR4. These data highlight the importance of membrane-anchored FGFR4 in assembling a multiprotein FGFR4 complex with NCAM and N-cadherin playing pivotal functions in maintaining normal cell adhesion. Disruption of distinct NCAM/N-cadherin pro-adhesive complexes by tumor-derived FGFR4 isoform provides a novel mechanism beyond ligand independence that explains the pathobiology of proliferative and infiltrative but non-metastatic neoplasms.
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