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RhoB is stabilized by transforming growth factor beta and antagonizes transcriptional activation
M E Engel1, P K Datta, H L Moses
1Department of Cell Biology and the Vanderbilt Cancer Center, Vanderbilt University, Nashville, Tennessee 37232-6838, USA.
Abstract:
Transforming growth factor beta (TGF-beta) is the prototype for an evolutionarily conserved superfamily of secreted factors implicated in diverse biological phenomena. The pleiotropic responses to TGF-beta are initiated by a heteromeric receptor complex that binds and phosphorylates downstream effectors. Among these, the Smads have been extensively studied. However, less attention has been directed toward alternative downstream effectors and their participation in TGF-beta signal transduction. We show that TGF-beta promotes accumulation of the labile monomeric GTPase RhoB by antagonizing its normal proteolytic destruction, presumably via the 26 S proteasome. RhoB accumulates in its isoprenylated form. Transient overexpression of wild type RhoB but not its dominant negative mutant RhoB-N19 antagonizes TGF-beta-mediated transcriptional activation. These results suggest a novel mechanism of regulation by TGF-beta and implicate RhoB as a negative regulator of TGF-beta signal transduction.
Insights
Transforming growth factor beta (TGF-beta) signaling involves the Smad pathway, but alternative effectors are less understood. This study reveals RhoB acts as a novel negative regulator in TGF-beta signal transduction.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Protein regulation
Background:
- Transforming growth factor beta (TGF-beta) is a key secreted factor regulating numerous biological processes.
- TGF-beta signaling is primarily mediated by the Smad protein family.
- Alternative downstream effectors of TGF-beta signaling remain underexplored.
Purpose of the Study:
- To investigate novel downstream effectors of TGF-beta signaling.
- To elucidate the role of RhoB in TGF-beta signal transduction.
Main Methods:
- Investigated the effect of TGF-beta on RhoB protein levels.
- Assessed the impact of RhoB overexpression on TGF-beta-mediated transcriptional activation.
- Utilized dominant-negative RhoB mutants to probe functional roles.
Main Results:
- TGF-beta promotes the accumulation of the labile monomeric GTPase RhoB by inhibiting its degradation via the 26S proteasome.
- Accumulated RhoB is found in its isoprenylated form.
- Overexpression of wild-type RhoB, but not a dominant-negative mutant, antagonizes TGF-beta-induced transcriptional activation.
Conclusions:
- TGF-beta utilizes a novel regulatory mechanism involving the stabilization of RhoB.
- RhoB functions as a negative regulator of TGF-beta signal transduction, providing a new layer of pathway control.