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J. Cell Biol. 173 (2): 291-299

Copyright © 2006 by the Rockefeller University Press.

Article

A kinase-deficient TrkC receptor isoform activates Arf6–Rac1 signaling through the scaffold protein tamalin

Pedro F. Esteban1, Hye-Young Yoon2, Jodi Becker1, Susan G. Dorsey1, Paola Caprari1, Mary Ellen Palko1, Vincenzo Coppola1, H. Uri Saragovi3, Paul A. Randazzo2, , and Lino Tessarollo1

1 Neural Development Group, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702
2 Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD 20892
3 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada H3G 1Y6

Correspondence to Lino Tessarollo: tessarol{at}ncifcrf.gov

Abstract: Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation of the kinase-active Trk receptors and the p75 neurotrophin receptor. Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. We show that the neurotrophin-3 (NT3) TrkCT1-truncated receptor binds to the scaffold protein tamalin in a ligand-dependent manner. Moreover, NT3 initiation of this complex leads to activation of the Rac1 GTPase through adenosine diphosphate-ribosylation factor 6 (Arf6). At the cellular level, NT3 binding to TrkCT1–tamalin induces Arf6 translocation to the membrane, which in turn causes membrane ruffling and the formation of cellular protrusions. Thus, our data identify a new signaling pathway elicited by the kinase-deficient TrkCT1 receptor. Moreover, we establish NT3 as an upstream regulator of Arf6.

Abbreviations used in this paper: Arf, ADP-ribosylation factor; ARNO, Arf nucleotide-binding site opener; coIP, coimmunoprecipitation; HEK, human embryonic kidney; PDZ, Psd-95/Dlg/ZO1.

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