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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    ABSTRACT: Neurotrophins (NTs) and their receptors play a key role in neurogenesis and survival. The TRK (tropomyosin-related kinase) receptor protein tyrosine kinases (TRKA, TRKB, TRKC) are high-affinity NT receptors that are expressed in a variety of human tissues. Their role in normal and malignant hematopoiesis is poorly understood. In a prospective study involving 94 adult patients we demonstrate for the first time cell-surface expression of the 3 TRKs and constitutive activation in blasts from patients with de novo or secondary acute leukemia. At least one TRK was expressed in 55% of the analyzed cases. We establish a clear correlation between the TRK expression pattern and FAB classification. Although only few point mutations were found in TRK sequences by reverse-transcriptase-polymerase chain reaction (RT-PCR), we observed coexpression of BDNF (ligand for TRKB) in more than 50% of TRKB(+) cases (16/30). Activation of TRKA or TRKB by NGF and BDNF, respectively, efficiently rescued murine myeloid cells from irradiation-induced apoptosis. Coexpression of TRKB/BDNF or TRKA/NGF in murine hematopoietic cells induced leukemia. Moreover, activation of TRKs was important for survival of both human and murine leukemic cells. Our findings suggest that TRKs play an important role in leukemogenesis and may serve as a new drug target.
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