The ETV6-NTRK3 chimeric tyrosine kinase suppresses TGF-β signaling by inactivating the TGF-β type II receptor

doi:10.1073/pnas.0503137102

The ETV6-NTRK3 chimeric tyrosine kinase suppresses TGF-β signaling by inactivating the TGF-β type II receptor

^*Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-5055; ^‡Division of Life Sciences, Kangwon National University, Chuncheon 200-701, Korea; ^§Department of Pathology, British Columbia's Children's Hospital, Vancouver, BC, Canada V6H 3V4; ^¶Korea Research Institute of Bioscience and Biotechnology, Daejon 305-806, Korea; ^∥Division of Oncology, Children's Hospital of Philadelphia, Department of Pediatrics and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and ^†Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA 90033

Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA (received for review April 15, 2005)

Abstract

An emerging theme in cancer biology is that although some malignancies occur through the sequential acquisition of different genetic alterations, certain dominantly acting oncoproteins such as those associated with chromosomal translocations have multiple functions and do not require additional mutations for cell transformation. The ETV6-NTRK3 (EN) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages, functions as a constitutively active protein tyrosine kinase. Here, we show that EN suppresses TGF-β signaling by directly binding to the type II TGF-β receptor, thereby preventing it from interacting with the type I TGF-β receptor. This activity requires a functional EN protein tyrosine kinase, and type II TGF-β receptor appears to be a direct target of EN. Our findings provide evidence for a previously undescribed mechanism by which oncogenic tyrosine kinases can block TGF-β tumor suppressor activity.

Footnotes

↵ ** To whom correspondence may be addressed. E-mail: kims{at}mail.nih.gov or psor{at}interchange.ubc.ca.
Author contributions: P.H.B.S. and S.-J.K. designed research, analyzed data, and wrote the paper; W.J., B.-C.K., C.T., H.-J.L., and S.P. performed research; and C.L.L., J.M.M., and T.J.T. contributed new reagents/analytic tools.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ActRIIA, activin R-IIA; ActRIIB, activin R-IIB; CFS, congenital fibrosarcoma; CMN, cellular mesoblastic nephroma; EN, ETV6-NTRK3; HA, hemagglutinin; MAPK, mitogen-activated protein kinase; MSCV, murine stem cell virus; PAI-1, plasminogen activation inhibitor-1; PI3K, phosphatidyl inositol-3-kinase; PTK, protein tyrosine kinase; SBE, Smad-binding element; TβRI, type I TGF-β receptor; TβRII, type II TGF-β receptor.