TrkC binds to the bone morphogenetic protein type II receptor to suppress bone morphogenetic protein signaling.
TrkC, a member of the tropomyosin-related kinase (Trk) family of neurotrophin receptors, is implicated in the growth and survival of human cancer tissues. TrkC is also a potent oncoprotein expressed in tumors derived from multiple cell lineages, and functions as an active protein tyrosine kinase by neurotrophin-3 (NT-3). We previously reported that TrkC plays an essential role in tumor growth and metastasis in a murine cancer cell line. Here, we report that expression of TrkC suppresses bone morphogenetic protein 2 (BMP-2)-induced Smad1 phosphorylation and transcriptional activation. In the highly metastatic CT26 murine colon cancer cell line, which expresses endogenous TrkC, silencing TrkC expression by small interfering RNA significantly enhanced BMP-2-induced Smad1 phosphorylation and restored BMP-2 growth inhibitory activity. In contrast, expression of TrkC in RIE-1 cells, in which TrkC is not expressed, completely suppressed BMP-2 transcriptional activation. Furthermore, we showed that TrkC directly binds to the BMP type II receptor (BMPRII), thereby preventing it from interacting with the BMPRI. This activity requires a functional TrkC protein tyrosine kinase, and the BMPRII seems to be a direct target of TrkC. Our findings provide evidence for a previously unknown mechanism by which TrkC, a neuronal receptor, can block BMP tumor-suppressor activity.
Jin
Wook
W
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Yun
Chohee
C
Kim
Hae-Suk
HS
Kim
Seong-Jin
SJ
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D023102:Anoikis / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D020812:Receptor, trkC / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D015533:Transcriptional Activation
D019485:Bone Morphogenetic Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D020812:Receptor, trkC; D052006:Bone Morphogenetic Protein Receptors, Type II