Abstract
BackgroundTumors expressing a transforming growth factor-beta type I receptor (TβRI) mutant with sequence deletions in a nine-alanine (9A) stretch of the signal peptide are reported to be highly associated with disease progression. Expression of this mutant could interfere with endogenous TGFβ signaling in the cell. However, little is known about the importance of the remaining part of the signal peptide on the cellular function of TβRI.ResultsWe cloned and identified four new in-frame deletion variants of TβRI, designated DM1 to DM4, in pleural effusion-derived tumor cells. Intriguingly, DM1 and DM2, with a small region truncated in the putative signal peptide of TβRI, had a serious defect in their protein expression compared with that of the wild-type receptor. Using serial deletion mutagenesis, we characterized a region encoded by nucleotides 16–51 as a key element controlling TβRI protein expression. Consistently, both DM1 and DM2 have this peptide deleted. Experiments using cycloheximde and MG132 further confirmed its indispensable role for the protein stability of TβRI. In contrast, truncation of the 9A-stretch itself or a region downstream to the stretch barely affected TβRI expression. However, variants lacking a region C-terminal to the stretch completely lost their capability to conduct TGFβ-induced transcriptional activation. Intriguingly, expression of DM3 in a cell sensitive to TGFβ made it significantly refractory to TGFβ-mediated growth inhibition. The effect of DM3 was to ablate the apoptotic event induced by TGFβ.ConclusionWe identified four new transcript variants of TβRI in malignant effusion tumor cells and characterized two key elements controlling its protein stability and transcriptional activation. Expression of one of variants bestowed cancer cells with a growth advantage in the presence of TGFβ. These results highlight the potential roles of some naturally occurring TβRI variants on the promotion of tumor malignancy.
Highlights
Tumors expressing a transforming growth factor-beta type I receptor (TβRI) mutant with sequence deletions in a nine-alanine (9A) stretch of the signal peptide are reported to be highly associated with disease progression
The data suggest that the insensitivity of effusion tumor cells to transforming growth factor β (TGFβ) may be caused by defects in the protein integrity of TGFβ type I receptor (TβRI)
(page number not for citation purposes) http://www.biomedcentral.com/1471-2199/8/72 knowledge to the molecular understanding of its protein expression and receptor function and provides an alternative molecular target for monitoring disease progression. These data demonstrate that a small deletion in the putative signal peptide of TβRI is a common feature for the pleural effusion-derived tumor cells we have examined so far, but this is not found in normal control cells
Summary
Tumors expressing a transforming growth factor-beta type I receptor (TβRI) mutant with sequence deletions in a nine-alanine (9A) stretch of the signal peptide are reported to be highly associated with disease progression. TGFβ binds to its cell surface TβRII, followed by the recruitment and phosphorylation of TβRI on a juxtamembrane glycine/serine (GS)rich domain This phosphorylation results in the association of R-Smads (Smad and Smad3) with a shared partner, Smad, to form heterotrimers that undergo nuclear translocation to regulate TGFβ-responsive genes. The putative function of TβRIII in these events is to facilitate ligand binding to TβRI and TβRII [2] Among these TGFβ receptors, the type I plays a pivotal role in conducting the TGFβ stimulus from cell surface into the nucleus to deliver various biological outcomes. Functional disruption, mutation, or aberrant expression of the TGFβ type I receptor gene (Tgfbr1) is frequently associated with human diseases, including cancers [3,4,5,6]
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