TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling

Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Oncogene (Impact Factor: 8.46). 06/2007; 26(55):7684-7691. DOI: 10.1038/sj.onc.1210571


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-β (TGF-β) signaling by directly binding to the type II TGF-β receptor (TβRII). Here, we report that expression of TrkC also suppresses TGF-β-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-β-induced Smad2/3 phosphorylation and restored TGF-β growth inhibitory activity. In contrast, expression of TrkC in 67NR cells, in which TrkC is not expressed, suppressed TGF-β transcriptional activation. Moreover, we show that TrkC directly binds to the TβRII, thereby preventing it from interacting with the type I TGF-β receptor (TβRI). These results indicate that TrkC is an inhibitor of TGF-β tumor suppressor activity.

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    • "The proto-oncogene TrkC/NTRK3 is a receptor tyrosine kinase that contains an intronic RE1 site and is derepressed by CDYL RNAi in TLM-HMEC (Figure 2F). TrkC plays a critical role in neurogenesis, cancers of the neural lineage (Nakagawara, 2001), and other types of cancers (Jin et al., 2007; McGregor et al., 1999). We found that stable transgenic expression of TrkC in TLM-HMEC induced cellular transformation , identifying TrkC as a candidate oncogene in these cells (Figure 3E). "
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