The ETV6-NTRK3 chimeric tyrosine kinase suppresses TGF-beta signaling by inactivating the TGF-beta type II receptor.
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 I TGF-beta receptor. This activity requires a functional EN protein tyrosine kinase, and type II 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.
Jin
Wook
W
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-5055, USA.
Kim
Byung-Chul
BC
Tognon
Cristina
C
Lee
Ho-Jae
HJ
Patel
Sejal
S
Lannon
Chris L
CL
Maris
John M
JM
Triche
Timothy J
TJ
Sorensen
Poul H B
PH
Kim
Seong-Jin
SJ
D030201:Activin Receptors, Type I / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D020812:Receptor, trkC; D000097764:ETS Translocation Variant 6 Protein
D030201:Activin Receptors, Type I; D015514:Oncogene Proteins, Fusion; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C484319:ETV6-NTRK3 fusion protein, human; D020812:Receptor, trkC; D000097764:ETS Translocation Variant 6 Protein