Analysis of SHP-1-mediated down-regulation of the TRK-T3 oncoprotein identifies Trk-fused gene (TFG) as a novel SHP-1-interacting protein.
SHP-1 is a cytoplasmic SH2 domain containing protein-tyrosine phosphatase (PTP) involved in the negative regulation of multiple signaling pathways in hematopoietic, nervous, and epithelial cells. The thyroid TRK-T3 oncogene consists of the NTRK1 tyrosine kinase domain fused in-frame with sequences of the TFG (TRK-fused gene), encoding a protein of unknown function. TFG contains a coiled-coil domain responsible for TRK-T3 oligomerization. In addition, recent analysis of the sequences outside of the coiled-coil domain suggested possible interactions with other proteins. Based on the presence of a putative SHP-1 SH2-binding site within the TFG sequences, we have investigated the role of the SHP-1 phosphatase in TRK-T3 oncoprotein signaling. In this study we show that SHP-1 interacts with and down-regulates TRK-T3. We provide evidence that SHP-1 SH2 and catalytic domains, respectively, associate with the TFG- and NTRK1-derived portions of TRK-T3. Our data contribute to the definition of cellular mechanisms involved in thyroid tumorigenesis. Moreover, it reveals TFG as a novel protein able to modulate SHP-1 activity.
Roccato
Emanuela
E
Department of Experimental Oncology Operative Unit Molecular Mechanisms of Cancer Growth and Progression, Istituto Nazionale Tumori, Via G. Venezian, 1 20133 Milan, Italy.
Miranda
Claudia
C
Raho
Giovanna
G
Pagliardini
Sonia
S
Pierotti
Marco A
MA
Greco
Angela
A
D000818:Animals; D002384:Catalysis; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000166:cytology; D051379:Mice; D016296:Mutagenesis; D041681:NIH 3T3 Cells; D017434:Protein Structure, Tertiary; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020917:Receptor, trkA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000503:physiopathology; D014443:Tyrosine / Q000378:metabolism; D033921:Vesicular Transport Proteins
D047908:Intracellular Signaling Peptides and Proteins; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011506:Proteins; D020917:Receptor, trkA; D014443:Tyrosine; C096163:TFG protein, human; D033921:Vesicular Transport Proteins; C509249:PTPN6 protein, human; C509248:Ptpn6 protein, mouse