Only the substitution of methionine 918 with a threonine and not with other residues activates RET transforming potential.
Specific point-mutations of the RET receptor tyrosine kinase protooncogene are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carcinoma (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 substituted Met918 with four different residues and found that RET acquired transforming activity only when Met918 was substituted with a threonine. However, 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), immmediate-early response 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 transforming pathway.
Cirafici
A M
AM
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli Federico II,Italy.
Salvatore
G
G
De Vita
G
G
Carlomagno
F
F
Dathan
N A
NA
Visconti
R
R
Melillo
R M
RM
Fusco
A
A
Santoro
M
M
D016475:3T3 Cells; D000818:Animals; D018276:Carcinoma, Medullary / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D029721:Drosophila Proteins; D004789:Enzyme Activation; D008715:Methionine; D051379:Mice; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics*; D010766:Phosphorylation; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D013329:Structure-Activity Relationship; D013964:Thyroid Neoplasms / Q000235:genetics; D014162:Transfection
D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D008715:Methionine; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse