Leucine zipper-mediated dimerization is essential for the PTC1 oncogenic activity.
The PTC1 chimeric oncogene is generated by the fusion of the tyrosine kinase domain of the RET proto-oncogene to the 5'-terminal region of another gene named H4 (D10S170). This oncogene has been detected only in human papillary thyroid carcinomas. We have previously demonstrated that the putative leucine zipper in the N-terminal region of H4 can mediate oligomerization of the PTC1 oncoprotein in vitro. In this study, we further demonstrated that the PTC1 oncoprotein forms a dimer in vivo, and the leucine zipper is responsible for this dimerization. The H4 leucine zipper-mediated dimerization is essential for tyrosine hyperphosphorylation and the transforming activity of the PTC1 oncoprotein. Introducing a loss-of-function PTC1 mutant into PTC1-transformed NIH3T3 cells suppressed the transforming activity of PTC1 and reversed the transformed phenotype of these cells, presumably by forming inactive heterodimers between the two forms of PTC1. Taken together, these data indicate that constitutive dimerization of the PTC1 oncoprotein is essential for PTC1 transforming activity and suggest that constitutive oligomerization acquired by rearrangement or by point mutations may be a general mechanism for the activation of receptor tyrosine kinase oncogenes.
Tong
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Q
Department of Physiology and the Department of Internal Medicine, Ohio State University, Columbus, Ohio 43210, USA.
Xing
S
S
Jhiang
S M
SM
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D006801:Humans; D016350:Leucine Zippers; D051379:Mice; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010766:Phosphorylation; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases; D000090063:Proto-Oncogene Mas; D014443:Tyrosine / Q000378:metabolism
C000715470:MAS1 protein, human; D015514:Oncogene Proteins, Fusion; D000090063:Proto-Oncogene Mas; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human