TY - JOUR
T1 - Role of the TFG N-terminus and coiled-coil domain in the transforming activity of the thyroid TRK-T3 oncogene
AU - Greco, Angela
AU - Fusetti, Lisa
AU - Miranda, Claudia
AU - Villa, Riccardo
AU - Zanotti, Simona
AU - Pagliardini, Sonia
AU - Pierotti, Marco A.
PY - 1998/2/12
Y1 - 1998/2/12
N2 - The thyroid TRK-T3 oncogene results from the fusion of the tyrosine kinase (TK) domain of NTRK1 (one of the receptors for the Nerve Growth Factor) on chromosome 1 to sequences of a novel gene, TFG, on chromosome 3. The 68 kDa TRK-T3 fusion oncoprotein displays a constitutive tyrosine kinase activity resulting in its capability to transform mouse NIH3T3 cells. The TFG portion of TRK-T3 contains a coiled-coil domain most likely responsible for the constitutive, ligand-independent activation of the receptor tyrosine kinase activity. We have previously shown that TRK-T3 oncoprotein forms, in vivo, complexes of three or four molecules. By mean of different experimental approaches, we show here that TRK-T3 activity depends on oligomers formation. In addition, the analysis of different TRK-T3 mutants indicates that the TFG coiled-coil domain and its N-terminal region are both required for the activation and the fully transforming activity of the TRK-T3 oncoprotein, although, most likely, they play a role in different steps of the transforming process. The deletion of the coiled-coil domain abrogates the oligomers formation leading to a constitutive activation; the deletion of the N-terminal region, although not affecting phosphorylation and complexes formation, abrogates transformation, thus suggesting a role in cellular localization and/or interaction with substrata.
AB - The thyroid TRK-T3 oncogene results from the fusion of the tyrosine kinase (TK) domain of NTRK1 (one of the receptors for the Nerve Growth Factor) on chromosome 1 to sequences of a novel gene, TFG, on chromosome 3. The 68 kDa TRK-T3 fusion oncoprotein displays a constitutive tyrosine kinase activity resulting in its capability to transform mouse NIH3T3 cells. The TFG portion of TRK-T3 contains a coiled-coil domain most likely responsible for the constitutive, ligand-independent activation of the receptor tyrosine kinase activity. We have previously shown that TRK-T3 oncoprotein forms, in vivo, complexes of three or four molecules. By mean of different experimental approaches, we show here that TRK-T3 activity depends on oligomers formation. In addition, the analysis of different TRK-T3 mutants indicates that the TFG coiled-coil domain and its N-terminal region are both required for the activation and the fully transforming activity of the TRK-T3 oncoprotein, although, most likely, they play a role in different steps of the transforming process. The deletion of the coiled-coil domain abrogates the oligomers formation leading to a constitutive activation; the deletion of the N-terminal region, although not affecting phosphorylation and complexes formation, abrogates transformation, thus suggesting a role in cellular localization and/or interaction with substrata.
KW - Coiled-coil domain
KW - Oncogenic transformation
KW - TRK oncogenes
UR - http://www.scopus.com/inward/record.url?scp=0032510108&partnerID=8YFLogxK
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M3 - Article
C2 - 9488046
AN - SCOPUS:0032510108
VL - 16
SP - 809
EP - 816
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 6
ER -