EXPRESSION OF MULTIPLE ENDOCRINE NEOPLASIA 2B RET IN NEUROBLASTOMA-CELLS ALTERS CELL-ADHESION IN-VITRO, ENHANCES METASTATIC BEHAVIOR IN-VIVO, AND ACTIVATES JUN KINASE

Point mutations, deletions, and recombinations of the RET proto-oncoge ne are associated with several inherited human diseases of neural cres t-derived cells: Hirschsprung's disease, familial medullary thyroid ca rcinoma, and the multiple endocrine neoplasia (MEN) syndromes, types 2 A and 2B, RET expression is restricted to normal and malignant cells o f neural crest origin, such as human neuroblastoma cells. To better un derstand 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 l ines overexpressing MEN2B RET demonstrated a marked increase in the ce ll 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 ce lls had increased autokinase activity, whereas MEN2B transfectant cell s demonstrated selective activation of the mitogen-activated protein k inase, Jun kinase-1 (Jnk1). These results indicate a biochemical signa ling pathway that may link oncogenic RET with the metastatic process.