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TFG-1 function in protein secretion and oncogenesis

Nature Cell Biology volume 13, pages 550–558 (2011)Cite this article

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Abstract

Export of proteins from the endoplasmic reticulum in COPII-coated vesicles occurs at defined sites that contain the scaffolding protein Sec16. We identify TFG-1, a new conserved regulator of protein secretion that interacts directly with SEC-16 and controls the export of cargoes from the endoplasmic reticulum in Caenorhabditis elegans. Hydrodynamic studies indicate that TFG-1 forms hexamers that facilitate the co-assembly of SEC-16 with COPII subunits. Consistent with these findings, TFG-1 depletion leads to a marked decline in both SEC-16 and COPII levels at endoplasmic reticulum exit sites. The sequence encoding the amino terminus of human TFG has been previously identified in chromosome translocation events involving two protein kinases, which created a pair of oncogenes. We propose that fusion of these kinases to TFG relocalizes their activities to endoplasmic reticulum exit sites, where they prematurely phosphorylate substrates during endoplasmic reticulum export. Our findings provide a mechanism by which translocations involving TFG can result in cellular transformation and oncogenesis.

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Figure 1: C. elegans TFG-1 interacts with the endoplasmic reticulum exit-site component SEC-16.
Figure 2: TFG-1 localizes to endoplasmic reticulum exit sites that are juxtaposed to the Golgi.
Figure 3: TFG-1 regulates SEC-16 levels on endoplasmic reticulum exit sites.
Figure 4: The N terminus of TFG-1 mediates its oligomerization.
Figure 5: TFG-1 is required for COPII recruitment and protein secretion.
Figure 6: Human TFG functions at endoplasmic reticulum exit sites and binds to Sec16.
Figure 7: Targeting of the NTRK1 kinase domain to endoplasmic reticulum exit sites is sufficient to activate NTRK1-mediated downstream signalling.

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  • 11 April 2011

    In the version of this Article initially published online, the title was incorrect. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported in part by grants from the NIH (1R01GM088151-01A1 to A.A. and P41RR011823 to J.R.Y.). We thank B. Weaver and P. Bertics for use of tissue culture facilities, R. Landick for use of a Gradient Master, K. Oegema for marker strains and antibodies, E. Chapman for use of Metamorph software and S. Koenig for help with RNAi. We also thank D. Stephens, P. Kiley and members of the Audhya laboratory for critically reading this manuscript.

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  1. Kristen Witte and Amber L. Schuh: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biomolecular Chemistry, University of Wisconsin–Madison Medical School, 1300 University Avenue, Madison, Wisconsin 53706, USA

    Kristen Witte, Amber L. Schuh, Jonathan R. Mayers & Anjon Audhya

  2. European Neuroscience Institute and Center for Molecular Physiology of the Brain (CMPB), 37077 Goettingen, Germany

    Jan Hegermann, Katrin Schwarze & Stefan Eimer

  3. Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA

    Ali Sarkeshik & John R. Yates III

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Contributions

K.W., A.L.S., S.E. and A.A. conceived and designed experiments. K.W., A.L.S., A.S., J.H., J.R.M., K.S., S.E. and A.A. carried out experiments and analysed data. S.E., J.R.Y. and A.A. contributed reagents, materials and analysis tools. A.A. wrote the paper.

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Correspondence to Anjon Audhya.

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Witte, K., Schuh, A., Hegermann, J. et al. TFG-1 function in protein secretion and oncogenesis. Nat Cell Biol 13, 550–558 (2011). https://doi.org/10.1038/ncb2225

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