Smad7 is required for TGF-β-induced activation of the small GTPase Cdc42

Abstract

Transforming growth factor β (TGF-β) is a potent regulator of cell growth and differentiation in many cell types. The Smad signaling pathway constitutes a main signal transduction route downstream of TGF-β receptors. The inhibitory Smads, Smad6 and Smad7, are considered to function as negative regulators of the TGF-β/Smad signaling cascade. In a previous study, we found that TGF-β induces rearrangements of the actin filament system in human prostate carcinoma cells and that this response requires the small GTPases Cdc42 and RhoA. On the basis of the current view on the function of Smad7 in TGF-β signaling, we hypothesized that Smad7 would function as a negative regulator of the TGF-β-induced activation of Cdc42 and RhoA, but instead we found that the reverse is the case; Smad7 is required for the TGF-β-induced activation of Cdc42 and the concomitant reorganization of the actin filament system. These observations propose a novel role for Smad7 in TGF-β-dependent activation of Rho GTPases.

BMP2 induction of actin cytoskeleton reorganization and cell migration requires PI3-kinase and Cdc42 activity

“…Our results indicate that the rapid appearance of cortical actin protrusions did not require protein synthesis, suggesting it is independent of transcriptional activity. Previous data also suggest a role for the inhibitory Smad7 in the delayed activation of Cdc42 (12-24 hours) by TGFβ in prostate carcinoma cells (Edlund et al, 2004). However, overexpression of Smad7 in mesenchymal C2C12 cells did not increase either basal or BMP-induced appearance of actin-enriched membrane protrusions (data not shown).…”

“…Moreover, expression of a dominant-negative form of Cdc42 or pretreatment with the PI3K inhibitors LY294002 or AS702630, both completely suppressed the BMP-induced appearance of actin protrusions. Although the pathway that leads to BMP2 activation of Cdc42 is still unknown, several reports indicate its requirement for cytoskeletal changes induced by BMPs or TGFβ (Edlund et al, 2002;Edlund et al, 2004;Lee-Hoeflich et al, 2004;Ricos et al, 1999). Depending on the cell type or stimuli, activation of Cdc42 has been described to be upstream or downstream of PI3K activity (Hawkins et al, 2006; Jimenez et al, Merlot and Firtel, 2003;Raftopoulou and Hall, 2004;Ridley et al, 2003).…”

A novel lentivirus for quantitative assessment of gene knockdown in stem cell differentiation

“…However, Smad7 has also been implicated in myogenicpromoting pathways. For example, Smad3 was shown to interact with SRF, 40 whereas Smad7 activated the small GTPase Cdc42 41 and interacted with myocardin in the nucleus-promoting myogenesis. 42 Therefore, our results may suggest that in HASMCs and BM-MSCs, Smad7 may participate in both anti-and pro-myogenic interactions, so that their overall action balances out the influence of these pathways.…”

Transforming Growth Factor β Induces Rosettes of Podosomes in Primary Aortic Endothelial Cells

“…Src, PI3K, and RhoGTPases are key proteins always involved in the complicated process of podosome formation (29). Since these three pathways can be regulated by TGF-␤ in other models (5,17,18,26,34,60), we examined their contributions to TGF-␤-induced podosome formation in endothelial cells. Src and PI3K catalytic activities were inhibited using a pharmacological approach, whereas RhoGTPases and Smad expression were suppressed using siRNAs.…”

“…Rho and phosphatidylinositide 3-kinase (PI3K) have been shown to be regulated by TGF-␤ in the context of the epithelium-to-mesenchyme transition (3), and Cdc42 and RhoA were found to be involved in TGF-␤-induced cytoskeletal remodeling in carcinomas (17,18) and skeletal muscle cells (34). Previous studies to explore the role of Rho GTPases in endothelial cytoskeletal reorganization revealed that constitutive activation of Cdc42 by the expression of V12Cdc42 triggered the formation of podosomes (37).…”