TGF-β Signaling

The transforming growth factor β (TGF-β) family of structurally related cytokines induces a multitude of effects that control proliferation, differentiation, migration and apoptosis of many different cell types. The basic TGF-β signaling system consists of two receptor serine/threonine protein kinases (receptor types I and II) and a family of direct receptor substrates (SMADs) that move into the nucleus upon phosphorylation and activation. The type II receptors are activators of the type I receptor, which in turn activate SMAD proteins.In vertebrates, the type I receptors for TGF-β, activin and nodal, recognize SMAD2 and SMAD3, whereas the bone morphogenic protein (BMP) and mullerian-inhibiting substance (MIS) receptors recognize SMAD 1,5 and 8. Receptor-mediated phosphorylation of this group of regulatory SMADs (R-SMADS) allows them to accumulate in the nucleus. The activated R-SMADs associate with the related proteins called co-SMADs (e.g. SMAD4) on their way to the nucleus. The co-SMADs are not receptor substrates but are required for many of the gene responses induced by R-SMADs.To function as intracellular mediators for TGF-β signals, the SMADs have to gain access to the receptors, undergo phosphorylation, form activated complexes, and accumulate in the nucleus. There are several levels at which the SMAD pathway can be regulated. The access of SMAD2 and SMAD3 to activated type 1 receptor is controlled by SMAD anchor for receptor activation (SARA). The levels of SMAD1 are controlled by the E3 Ubiquitin ligase SMAD ubiquitination regulatory factor-1 (SMURF-1). SMURFS 1 and 2 control the turnover of the TGF-β receptor and thereby the activation of SMADs. In addition to R-SMADs and co-SMADs, a third group of SMADs act antagonistically, inhibiting receptor-mediated activation of R-SMADs (e.g. SMAD6 and SMAD7). Another level of control of the SMAD pathway is via the regulation of nucleur accumulation of SMADs by the Ras-Extracellular signal kinase (ERK) pathway. Once in the nucleus, a SMAD complex may associate with transcriptional co-activators such as CREB binding protein (CBP) or transcriptional co-repressors such as TGF-β-induced factor homeobox 1 (TGIF) and histone deacetylases (HDAC). Trancriptional activation by SMADs results in a highly complex pattern of gene expression such as that seen in embryonic development. TGF-β exerts some of its biological effects independent of SMADs. Upon TGF-β induced receptor activation, the E3 ubiquitin ligase TRAF6 undergoes autoubiquitylation and subsequent activation of the TAK1-p38/JNK pathway.This pathway highlights the important molecular events involved in TGFβ signaling via SMAD proteins.