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The Signaling Adapters Fibroblast Growth Factor Receptor Substrate 2 and 3 Are Activated by the Thyroid TRK Oncoproteins

Department of Experimental Oncology (V.R., C.M., P.M., M.A.P., A.G.), Operative Unit "Molecular Mechanisms of Cancer Growth and Progression," Istituto Nazionale Tumori, 20133 Milan, Italy; and Laboratory of Neural Signaling (S.O.M.), Cell Biology Group, Robarts Research Institute, London, Ontario N6A 5K8, Canada

Address all correspondence and requests for reprints to: Angela Greco, Department of Experimental Oncology, Istituto Nazionale Tumori, 1 Via Venezian, 20133 Milan, Italy. E-mail: angela.greco{at}istitutotumori.mi.it.

The thyroid TRK oncogenes are generated by chromosomal rearrangements juxtaposing the neurotrophic tyrosine receptor kinase type 1 (NTRK1) tyrosine kinase domain to foreign activating sequences. TRK oncoproteins display a constitutive tyrosine kinase activity resulting in the capability to transform NIH3T3 cells. The TRK oncoproteins’ signal transduction has been in part elucidated, and it involves several signal transducers activated by the NGF-stimulated NTRK1 receptor. In this paper, we investigate the role of FRS2 and FRS3, two related adapter proteins activated by fibroblast growth factor and NTRK1 receptors, in the signaling of the thyroid TRK-T1 and TRK-T3 oncogenes. By a combination of in vitro and in vivo assays, we demonstrate that both fibroblast growth factor receptor substrate (FRS)2 and FRS3 are recruited and activated by TRK-T1 and TRK-T3. Interaction studies using different TRK-T3 mutants indicate that FRS3 is recruited by the same tyrosine residue interacting with Shc and FRS2. Expression studies show different expression patterns of the FRS adapters in normal and tumor thyroid samples: FRS3 is expressed in both normal and thyroid tumor samples, whereas FRS2 is not expressed in normal thyroid but is differentially expressed in some tumors. Altogether, our data indicate that the FRS2 and FRS3 adapters may have a role in thyroid carcinogenesis triggered by TRK oncogenes.

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