A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation.

Abstract	Receptor tyrosine kinases are integral components of cellular signaling pathways and are frequently deregulated in malignancies. The NTRK family of neurotrophin receptors mediate neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in oncogenesis. The ETV6-NTRK3 (EN) gene fusion occurs in human pediatric spindle cell sarcomas and secretory breast carcinoma, and encodes the oligomerization domain of the ETV6 transcription factor fused to the protein-tyrosine kinase domain of NTRK3. The EN protein functions as a constitutively active protein-tyrosine kinase with potent transforming activity in multiple cell lineages, and EN constitutively activates both the Ras-MAPK and phosphatidylinositol 3-kinase-Akt pathways. EN transformation is associated with constitutive tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Further, IRS-1 functions as the adaptor protein linking EN to downstream signaling pathways. However, the exact nature of the EN-IRS-1 interaction remains unknown. We now demonstrate that EN specifically binds the phosphotyrosine binding domain of IRS-1 via an interaction at the C terminus of EN. An EN mutant lacking the C-terminal 19 amino acids does not bind IRS-1 and lacks transforming ability. Moreover, expression of an IRS-1 polypeptide containing the phosphotyrosine binding domain acts in a dominant negative manner to inhibit EN transformation, and overexpression of IRS-1 potentiates EN transforming activity. These findings indicate that EN.IRS-1 complex formation through the NTRK3 C terminus is essential for EN transformation.
Authors	Chris L Lannon, Matthew J Martin, Cristina E Tognon, Wook Jin, Seong-Jin Kim, Poul H B Sorensen
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 8 Pg. 6225-34 (Feb 20 2004) ISSN: 0021-9258 [Print] United States
PMID	14668342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	DNA, Complementary DNA-Binding Proteins ETS translocation variant 6 protein ETV6-NTRK3 fusion protein, human IRS1 protein, human Insulin Receptor Substrate Proteins Irs1 protein, mouse Oncogene Proteins, Fusion Phosphoproteins Proto-Oncogene Proteins c-ets Repressor Proteins Phosphotyrosine Tyrosine Agar Phosphatidylinositol 3-Kinases Receptor, trkC
Topics	Agar (pharmacology) Amino Acid Sequence Animals Binding Sites Cell Differentiation Cell Line Cell Line, Tumor Cell Survival Cell Transformation, Neoplastic Conserved Sequence DNA, Complementary (metabolism) DNA-Binding Proteins (chemistry) Enzyme Activation Fibroblasts (metabolism) Genes, Dominant Genetic Vectors Humans Insulin Receptor Substrate Proteins Mice Mice, Nude Molecular Sequence Data Mutagenesis, Site-Directed NIH 3T3 Cells Neurons (metabolism) Oncogene Proteins, Fusion (chemistry, metabolism) Phosphatidylinositol 3-Kinases (metabolism) Phosphoproteins (chemistry, metabolism) Phosphotyrosine (chemistry) Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins c-ets Receptor, trkC (chemistry) Repressor Proteins (chemistry) Retroviridae (genetics) Sequence Homology, Amino Acid Signal Transduction Time Factors Tyrosine (chemistry, metabolism)

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