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J. Biol. Chem., Vol. 280, Issue 5, 3382-3389, February 4, 2005

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Analysis of SHP-1-mediated Down-regulation of the TRK-T3 Oncoprotein Identifies Trk-fused Gene (TFG) as a Novel SHP-1-interacting Protein^*

Emanuela Roccato, Claudia Miranda, Giovanna Raho, Sonia Pagliardini, Marco A. Pierotti, and Angela Greco¶

From the Department of Experimental Oncology Operative Unit Molecular Mechanisms of Cancer Growth and Progression, Istituto Nazionale Tumori, Via G. Venezian, 1 20133 Milan, Italy and the IFOM Foundation, The Firc Institute for Molecular Oncology Foundation, 20139 Milan, Italy

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.

Received for publication, July 6, 2004 , and in revised form, November 19, 2004.

^* This work was supported by AIRC (Italian Association for Cancer Research). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 39-02-2390-3222; Fax: 39-02-2390-2764; E-mail: angela.greco{at}istitutotumori.mi.it.

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