TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling
TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling
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DOI：
10.1038/sj.onc.1210571
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发表时间：
2007-12-06
期刊：
影响因子：
8
通讯作者：
Kim, S-J
中科院分区：
文献类型：
--
作者：
Jin, W.;Yun, C.;Kim, S-J
越来越多的证据表明，神经营养因子受体Trk家族成员TrkC的过表达可以驱动癌细胞的肿瘤发生、侵袭和转移能力。然而，对TrkC介导的肿瘤发生机制知之甚少。TrkC基因是Tel-TrkC（ETV 6-NTRK 3）嵌合酪氨酸激酶的伴侣，所述嵌合酪氨酸激酶是在源自多个细胞谱系的肿瘤中表达的有效癌蛋白。最近，我们已经表明ETV 6-NTRK 3通过直接结合II型TGF-β受体（TbRII）来抑制转化生长因子-β（TGF-β）信号传导。在这里，我们报告说，表达的TrkC也抑制TGF-β诱导的Smad 2/3磷酸化和转录激活。在表达内源性TrkC的高转移性4 T1乳腺肿瘤细胞系中，通过小干扰RNA沉默TrkC表达显著增强了TGF-β诱导的Smad 2/3磷酸化，并恢复了TGF-β生长抑制活性。相反，在不表达TrkC的67 NR细胞中表达TrkC抑制TGF-β转录激活。此外，我们表明，TrkC直接结合TbRII，从而防止它与I型TGF-β受体（T β RI）相互作用。这些结果表明，TrkC是TGF-β肿瘤抑制活性的抑制剂。
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 (TbRII). 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-b 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 TbRII, thereby preventing it from interacting with the type I TGF-beta receptor (T beta RI). These results indicate that TrkC is an inhibitor of TGF-beta tumor suppressor activity.