Point mutations, deletions, and recombinations of the RET proto-oncogene are associated with several inherited human diseases of neural crest-derived cells: Hirschsprung's disease, familial medullary thyroid carcinoma, and the multiple endocrine neoplasia (MEN) syndromes, types 2A and 2B. RET expression is restricted to normal and malignant cells of neural crest origin, such as human neuroblastoma cells. To better understand the role of the activated RET oncogene in neural crest cells, we transfected two adherent human neuroblastoma tumor cell lines with oncogenic MEN2 mutant RET cDNAs. Transfectant clones from both cell lines overexpressing MEN2B RET demonstrated a marked increase in the cell fraction growing in suspension. Both control and MEN2B cells formed tumors at the site of injection in all cases. However, mice injected with MEN2B cells developed lung metastases at a much higher frequency than control mice. Only RET protein derived from MEN2A transfectant cells had increased autokinase activity, whereas MEN2B transfectant cells demonstrated selective activation of the mitogen-activated protein kinase, Jun kinase-1 (Jnk1). These results indicate a biochemical signaling pathway that may link oncogenic RET with the metastatic process.

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This work was supported by grants from the National Health & Medical Research Council (to G. M. M., M. D. N., M. H.), New South Wales State Cancer Council (to G. M. M., M. D. N., M. H.), Sydney Children's Hospital Foundation (to G. M. M.), Queensland Cancer Fund (to J. F. H.), Royal Children's Hospital Foundation (to J. F. H.), and the Childrens Cancer Foundation Australia (to G. M. M., M. D. N., M. H.), A. E. P. is supported by an Australian Postgraduate Award.

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