MAP-kinase activity necessary for TGFbeta1-stimulated mesangial cell type I collagen expression requires adhesion-dependent phosphorylation of FAK tyrosine 397.

The signals mediating transforming growth factor beta (TGFbeta)-stimulated kidney fibrogenesis are poorly understood. We previously reported TGFbeta-stimulated, Smad-mediated collagen production by human kidney mesangial cells, and that ERK MAP kinase activity optimizes collagen expression and enhances phosphorylation of the Smad3 linker region. Furthermore, we showed that disrupting cytoskeletal integrity decreases type I collagen production.

Cell phenotype-specific down-regulation of Smad3 involves decreased gene activation as well as protein degradation.

Signaling by transforming growth factor-beta (TGF-beta), a regulator of several biological processes, including renal fibrosis, is mediated, in part, by the Smad proteins. Tight control of Smad level and activity is critical for proper TGF-beta biological functions. Here, we have investigated the mechanisms involved in regulating Smad3 expression.

TGF-beta receptor-binding proteins: complex interactions.

Members of the Smad protein family are fundamental downstream mediators of TGF-beta signals. However, the basic, linear Smad signaling pathway is unlikely to be the sole contributor to the plethora of cell type-specific TGF-beta responses. Investigators have identified a number of molecules that interact with the TGF-beta receptors (TbetaRs) and may explain, at least in part, the tight regulation of TGF-beta effects.

The role of internalization in transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells.

Recent data investigating the role of the Smad anchor for receptor activation (SARA) in TGF-beta signaling have suggested that it has a crucial function in both aiding the recruitment of Smad to the TGF-beta receptor, and ensuring appropriate subcellular localization of the activated receptor-bound complex. The FYVE domain in SARA directs its localization to early endosomal compartments where it can interact with both the TGF-beta receptors and Smads. However, the necessity of endocytosis in the TGF-beta response remains controversial.

The phosphatidylinositol 3-kinase/Akt pathway enhances Smad3-stimulated mesangial cell collagen I expression in response to transforming growth factor-beta1.

Transforming growth factor (TGF)-beta has been associated with renal glomerular matrix accumulation. We previously showed that Smad3 promotes COL1A2 gene activation by TGF-beta1 in human glomerular mesangial cells. Here, we report that the PI3K/Akt pathway also plays a role in TGF-beta1-increased collagen I expression.

Smad3 and PKCdelta mediate TGF-beta1-induced collagen I expression in human mesangial cells.

Transforming growth factor (TGF)-beta has been associated with fibrogenesis in clinical studies and animal models. We previously showed that Smad3 promotes COL1A2 gene activation by TGF-beta1 in human mesangial cells. In addition to the Smad pathway, it has been suggested that TGF-beta1 could also activate more classical growth factor signaling.

TGF-beta signal transduction and mesangial cell fibrogenesis.

Transforming growth factor-beta (TGF-beta) is closely associated with progressive renal fibrosis. Significant progress has been accomplished in determining the cellular signaling pathways that are activated by TGF-beta. This knowledge is being applied to glomerular mesangial cell models of extracellular matrix (ECM) accumulation.