Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 45, Pages 16239-16244Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0503137102
Keywords
chromosomal translocation; congenital fibrosarcoma; TGF-beta receptor
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Funding
- Intramural NIH HHS Funding Source: Medline
- NCI NIH HHS [U01 CA088199, Z01 BC005617-17, U01 CA88199] Funding Source: Medline
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An emerging theme in cancer biology is that although some malignancies occur through the sequential acquisition of different genetic alterations, certain dominantly acting oncoproteins such as those associated with chromosomal translocations have multiple functions and do not require additional mutations for cell transformation. The ETV6-NTRK3 (EN) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages, functions as a constitutively active protein tyrosine kinase. Here, we show that EN suppresses TGF-beta signaling by directly binding to the type II TGF-beta receptor, thereby preventing it from interacting with the type ITGF-13 receptor. This activity requires a functional EN protein tyrosine kinase, and type 11 TGF-beta receptor appears to be a direct target of EN. Our findings provide evidence for a previously undescribed mechanism by which oncogenic tyrosine kinases can block TGF-beta tumor suppressor activity.
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