TrkC binds to the type II TGF-beta receptor to suppress TGF-beta signaling.
Growing evidence suggests that overexpression of TrkC, a member of the Trk family of neurotrophin receptors, could drive tumorigenesis, invasion and metastatic capability in cancer cells. However, relatively little is known about the mechanism of TrkC-mediated oncogenesis. The TrkC gene is a partner of the Tel-TrkC (ETV6-NTRK3) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages. Recently, we have shown that ETV6-NTRK3 suppresses transforming growth factor-beta (TGF-beta) signaling by directly binding to the type II TGF-beta receptor (TbetaRII). Here, we report that expression of TrkC also suppresses TGF-beta-induced Smad2/3 phosphorylation and transcriptional activation. Silencing TrkC expression by small interfering RNA in the highly metastatic 4T1 mammary tumor cell line expressing endogenous TrkC significantly enhanced TGF-beta-induced Smad2/3 phosphorylation and restored TGF-beta growth inhibitory activity. In contrast, expression of TrkC in 67NR cells, in which TrkC is not expressed, suppressed TGF-beta transcriptional activation. Moreover, we show that TrkC directly binds to the TbetaRII, thereby preventing it from interacting with the type I TGF-beta receptor (TbetaRI). These results indicate that TrkC is an inhibitor of TGF-beta tumor suppressor activity.
Jin
W
W
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Yun
C
C
Kwak
M-K
MK
Kim
T-A
TA
Kim
S-J
SJ
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020812:Receptor, trkC / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D020812:Receptor, trkC; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II