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

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