ONLY THE SUBSTITUTION OF METHIONINE-918 WITH A THREONINE AND NOT WITHOTHER RESIDUES ACTIVATES RET TRANSFORMING POTENTIAL

Specific point-mutations of the RET receptor tyrosine kinase protoonco gene ale responsible for the inheritance of multiple endocrine neoplas ia type 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carc inoma (FMTC). MEN2B is caused by the substitution of methionine 918 by a threonine in the tyrosine kinase (TK) domain of RET. This mutation converts RET into a dominant transforming oncogene. We have substitute d Met918 with four different residues and found that RET acquired tran sforming activity only when Met918 was substituted with a threonine. H owever, also when serine and valine, but not leucine or phenylalanine, were inserted in position 918, the RET TK function was activated and induced, especially in the case of the RET(918Ser), immediate-early re sponse genes. We conclude that the preservation of Met918 is critical for the control of RET kinase. However, only when a threonine residue is present in position 918, does RET efficiently couple with a transfo rming pathway.