TrkC binds to the type II TGF-beta receptor to suppress TGF-beta signaling.

Abstract

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.

• Authors: W Jin, C Yun, M-K Kwak, T-A Kim, S-J Kim
• Journal: Oncogene (Oncogene) Vol. 26 Issue 55 Pg. 7684-91 (Dec 06 2007) ISSN: 1476-5594 [Electronic] England
• PMID: 17546043 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• RNA, Small Interfering
• Receptors, Transforming Growth Factor beta
• Smad2 Protein
• Smad3 Protein
• Transforming Growth Factor beta
• Tumor Suppressor Proteins
• Receptor, trkC
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• Receptor, Transforming Growth Factor-beta Type II

Topics

• Animals
• Cell Line, Tumor
• Humans
• Mice
• NIH 3T3 Cells
• Protein Serine-Threonine Kinases (metabolism)
• RNA, Small Interfering (pharmacology)
• Receptor, Transforming Growth Factor-beta Type I
• Receptor, Transforming Growth Factor-beta Type II
• Receptor, trkC (antagonists & inhibitors, genetics, metabolism)
• Receptors, Transforming Growth Factor beta (metabolism)
• Signal Transduction
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Transcriptional Activation
• Transforming Growth Factor beta (antagonists & inhibitors, metabolism, pharmacology)
• Tumor Suppressor Proteins (antagonists & inhibitors, metabolism, pharmacology)