Kretzschmar, M., Doody, J. & Massague, J. Opposing BMP and EGF signalling pathways converge on the TGF- family mediator Smad1. Nature 389, 618-622

Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Nature (Impact Factor: 41.46). 11/1997; 389(6651):618-22. DOI: 10.1038/39348
Source: PubMed


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.

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    • "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). "
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    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.
    Cell Reports 10/2014; 9(2):688-700. DOI:10.1016/j.celrep.2014.09.020 · 8.36 Impact Factor
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    • "For example, in breast cancers Smad gene mutations are rare [21] [150] [151] 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 [157] [158] [159]. "
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    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
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    • "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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    ABSTRACT: Dlx3 is essential for osteoblast differentiation and bone formation, and its expression is regulated by bone morphogenetic protein-2 (BMP-2). However, the intimate mechanism of BMP-2 regulation of Dlx3 transcription in osteoblasts is still unknown. Considering the important roles of Smad5 and p38 in osteoblast differentiation, we hypothesized that Smad5 and p38 mediated BMP-2-induced Dlx3 transcription in osteoblasts. We found activation of Smad5 and p38 increased the expression of Dlx3, whereas knocking down Smad5 or inactivation of p38 inhibited BMP-2-induced Dlx3 expression. Both Smad5 and p38 were able to activate Dlx3 promoter activity and p38/Smad5 response elements were located from -698 to -368 in Dlx3 promoter. Two Smad5 binding sites (SBEI and SBEII, TGTCT box) were identified in this region by EMSA and ChIP assay. Deletions and mutagenesis study of the Dlx3 promoter region indicated that the TGTCT boxes are crucial for p38/Smad5-induced Dlx3 promoter activity. At last, we found a cross-talk between p38 and Smad5, and that activation of p38 is necessary for BMP-2-induced Smad5 phosphorylation and nuclear translocation. Overall, we provide a novel insight that BMP-2-induced Dlx3 expression is regulated by p38/Smad5 signaling pathway in osteoblasts. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 07/2014; 229(7). DOI:10.1002/jcp.24525 · 3.84 Impact Factor
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