TGF-β/activin and BMP pathways are modulated by MAPK signaling at a number. Of Transforming Growth Factor β superfamily signalling: Background matters.

Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focuses on recent advances in the understanding of the molecular and biochemical mechanisms of non-Smad pathways. In addition, functions of these non-Smad pathways are also discussed.

TGF-β-induced Erk activation and tyrosine phosphorylation The initial indication that TGF-β can activate the Erk MAPK pathway came from observations showing a rapid activation of p21 (Ras) by TGF-β in rat intestine or mink lung epithelial cells [, ]. Actix crack keygen idm 2017 full. The rapid GTP loading of Ras in response to TGF-β in the above epithelial cells may cause recruitment of Raf, a MAP kinase kinase kinase (MAP3K), to the plasma membrane and lead to activation of Erk through MEK1. Subsequently, rapid activation of Erk by TGF-β was observed in epithelial cells [], breast cancer cells [], and fibroblasts []. The kinetics of Erk phosphorylation induced by TGF-β varies with cell types and culture conditions. In some cell lines, a delayed response of Erk to TGF-β was reported, typically with the peak of Erk phosphorylation occurring hours after ligand stimulation, suggesting an indirect response requiring protein translation [].

In contrast, in other types of cells, activation can occur rapidly within 5–10 min of TGF-β stimulation, which is comparable to the time course of Erk activation by mitogenic factors such as EGF []. Although Smad-dependent transcriptional mechanism can account, at least in part, for the delayed activation of Erk by TGF-β, it does not explain the rapid activation of Erk by TGF-β. In the receptor tyrosine kinase (RTK)/Ras/Erk signaling pathway, binding of growth factors to their RTKs induces dimerization and activation of the RTK [, ]. This results in auto- and trans-phosphorylation of multiple tyrosine residues in the cytoplasmic domain of RTK. Once phosphorylated, these tyrosine residues serve as docking sites for numerous signaling molecules with either Src homology 2 (SH2) or phosphor-tyrosine binding (PTB) domains, such as Src and growth factor receptor binding protein 2 (Grb2).