The growth factor TGF-beta, bone morphogenetic proteins (BMPs) and related factors regulate cell proliferation, differentiation and apoptosis, controlling the development and maintenance of most tissues. Their signals are transmitted through the phosphorylation of the tumour-suppressor SMAD proteins by receptor protein serine/threonine kinases (RS/TKs), leading to the nuclear accumulation and transcriptional activity of SMAD proteins. Here we report that Smadl, which mediates BMP signals, is also a target of mitogenic growth-factor signalling through epidermal growth factor and hepatocyte growth factor receptor protein tyrosine kinases (RTKs). Phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of Smad1, and is catalysed by the Erk family of mitogen-activated protein kinases. In contrast to the BMP-stimulated phosphorylation of Smad1, which affects carboxy-terminal serines and induces nuclear accumulation of Smad1, Erk-mediated phosphorylation specifically inhibits the nuclear accumulation of Smad1. Thus, Smadl receives opposing regulatory inputs through RTKs and RS/TKs, and it is this balance that determines the level of Smad1 activity in the nucleus, and so possibly the role of Smad1 in the control of cell fate.
"Transforming growth factor b (TGF-b) receptors signal by phosphorylating carboxy-terminal serines of the transcription factors Smad1/5/8 (for bone morphogenetic proteins [BMPs]) or Smad2/3 (for TGF-b/activin). These receptor-activated Smads (R-Smads) then undergo a second set of phosphorylations in the linker region via activation of tyrosine kinase receptors such as those for fibroblast growth factor (FGF) and epidermal growth factor (EGF) (Kretzschmar et al., 1997; Pera et al., 2003; Sapkota et al., 2007; Fuentealba et al., 2007; Millet et al., 2009) or through nuclear CDK8 and CDK9 (Alarcó n et al., 2009; Gao et al., 2009; Aragó n et al., 2011). These prime phosphorylations by glycogen synthase kinase-3 (GSK3) that target R-Smads for proteasomal degradation (Fuentealba et al., 2007; Sapkota et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Smad4 is a major tumor suppressor currently thought to function constitutively in the transforming growth factor β (TGF-β)-signaling pathway. Here, we report that Smad4 activity is directly regulated by the Wnt and fibroblast growth factor (FGF) pathways through GSK3 and mitogen-activated protein kinase (MAPK) phosphorylation sites. FGF activates MAPK, which primes three sequential GSK3 phosphorylations that generate a Wnt-regulated phosphodegron bound by the ubiquitin E3 ligase β-TrCP. In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region. When MAPK is not activated, the Wnt and TGF-β signaling pathways remain insulated from each other. In Xenopus embryos, these Smad4 phosphorylations regulate germ-layer specification and Spemann organizer formation. The results show that three major signaling pathways critical in development and cancer are integrated at the level of Smad4.
"For example, in breast cancers Smad gene mutations are rare    suggesting that additional mechanisms for acquiring resistance to TGFí µí»½-mediated growth inhibition also exist. It has been shown that activation of the Ras oncogene and its downstream target Erk leads to the phosphorylation of Smad1, Smad2, and Smad3 in their linker region, thus inducing their retention in the cytoplasm and promoting their ubiquitin-dependent degradation   . "
[Show abstract][Hide abstract] ABSTRACT: Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.
Journal of Oncology 10/2014; 587193. DOI:10.1155/2015/587193
"Smad3 by ERK blocks their translocation to the nucleus resulting in inhibition of Smad-mediated transcription (Kretzschmar et al., 1997). However, in the present study, we used an antibody detecting the C-terminal phosphorylation of Smad5 and found that inhibition of p38 by SB203580 suppressed BMP-2-induced phosphorylation and nuclear translocation of Smad5, which means p38 promotes Smad5 C-terminal phosphorylation and nuclear translocation. "
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