Editors' ChoiceCancer

Another TGF-β Desensitization Strategy

Science Signaling  21 Jul 2009:
Vol. 2, Issue 80, pp. ec247
DOI: 10.1126/scisignal.280ec247

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-α 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]