Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 21 July 2009
Vol. 2, Issue 80, p. ec247
[DOI: 10.1126/scisignal.280ec247]


Cancer Another TGF-β Desensitization Strategy

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

Cancer cells become resistant to the antiproliferative effect of transforming growth factor–β (TGF-β) signaling by various mutational and epigenetic mechanisms. The extracellular signal–regulated kinase (ERK) pathway, which is up-regulated in many cancers, can down-regulate TGF-β signaling by affecting the activity or nuclear translocation of the TGF-β–regulated Smad transcription factors or their cofactors. Liu et al. report that the ERK signaling may also down-regulate TGF-β signaling by decreasing the abundance of functional receptor complexes on the cell surface. The metalloprotease TACE (TNF-{alpha} converting enzyme, also known as ADAM17), which is often highly abundant in cancer cells and is activated by ERK signaling, was required for the ERK-induced decrease in the amount of full-length type I TGF-β receptor (TGF-βR1) on the surface of CHO cells and the appearance of a truncated form of TGF-βR1. Neither TACE nor ERK signaling had any effect on the abundance of type II TGF-β receptors (TGF-βRIIs). Wild-type, but not catalytically inactive, TACE coexpressed with C-terminally tagged versions of TGF-βRI and TGF-βRII had no effect on TGF-βRII but did decrease the amount of full-length tagged TGF-βRI and caused a smaller TGF-βRI band to appear. TACE did not cleave the related type I receptors ALK1, ALK2, ALK3, ALK4, or ALK6. Depletion of TACE in several epithelial and cancer cell lines by siRNA also caused an increase in phosphorylation of the TGF-β–activated transcription factor Smad3 in response to TGF-β stimulation and increased the basal amount of TGF-βR1 on the cell surface. Because TACE was required for the decrease in phosphorylation of both Smad3 and Akt in CHO cells costimulated with TGF-β and an ERK pathway activator, TACE antagonized both Smad-dependent and Smad-independent TGF-β signaling. The authors model that ERK-activated TACE mediates shedding of the TGF-βR1 ectodomain, which reduces the number of receptor heterotetramers that can form to transduce signaling. The authors propose that such a mechanism might contribute to the reduced sensitivity to antiproliferative TGF-β signaling seen in some cancer cells.

C. Liu, P. Xu, S. Lamouille, J. Xu, R. Derynck, TACE-mediated ectodomain shedding of the type I TGF-β receptor downregulates TGF-β signaling. Mol. Cell. 35, 26–36 (2009). [PubMed]

Citation: A. M. VanHook, Another TGF-β Desensitization Strategy. Sci. Signal. 2, ec247 (2009).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882