CDK8/9 drive Smad transcriptional action, turnover and YAP interactions in BMP and TGFβ pathways

By Claudio R. Alarcón, A. Zaromytidou, Q. Xi, Sheng Gao, Jianzhong Yu, S. Fujisawa, A. Barlas, Alexandria N. Miller, K. Manova-Todorova, M. Macias and 3 more. Cell, 2009

754 citations recorded by the source corpus.

TGFβ and BMP receptor kinases activate Smad transcription factors by C-terminal phosphorylation. We have identified a subsequent agonist-induced phosphorylation that plays a central dual role in Smad transcriptional activation and turnover. As receptor-activated Smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by CDK8 and CDK9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote Smad transcriptional action, which in the case of Smad1, is mediated by the recruitment of YAP to the phosphorylated linker sites. An effector of the highly conserved Hippo organ size control pathway, YAP supports Smad1-dependent transcription and is required for BMP suppression of neural differentiation of mouse embryonic stem cells. The phosphorylated linker is ultimately recognized by specific ubiquitin ligases, leading to proteasome-mediated turnover of activated Smad proteins. Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal that is an integral part of canonical BMP and TGFβ pathways.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a0d07fa38c3d1b762f25fd526546b9ca2fef545f

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In Cell Biology

1. K. Guan
2. S. Piccolo
3. Fa-Xing Yu
4. M. Cordenonsi
5. G. Halder
6. H. Park
7. Jung-Soon Mo
8. S. Dupont

In Molecular Biology

1. K. Guan
2. Fa-Xing Yu
3. E. Batlle
4. S. Piccolo
5. M. Cordenonsi
6. Randy L. Johnson
7. J. Massagué
8. G. Halder

Citations in the corpus

• Dependency of colorectal cancer on a TGF-beta-driven programme in stromal cells for metastasis initiation (2012, background): “Yet, this genetic alteration did not impede the nuclear accumulation of p-SMADs (Figure 3B), as previously reported for other SMAD4 mutant cell lines (Alarcón et al., 2009; Liu et al., 1997).”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “YAP and TAZ were repeatedly isolated as binding proteins for Smads, key transducer of the TGF- and BMP signaling pathways (2, 207, 208).”
• Hippo signaling: growth control and beyond (2011, background): “In addition, binding of Yap to Smad1 enhances BMP signaling (Alarcon et al., 2009).”
• Control of Embryonic Stem Cell State (2011, background): “The CDK8 kinase subunit of the mediator complex can influence the activity of signaling transcription factors (Alarcon et al., 2009; Fryer et al., 2004; Gao et al., 2009; Taatjes, 2010).”
• The Hippo signaling pathway in stem cell biology and cancer (2014, positive): “Recently, the Hippo pathway has also emerged as a crucial regulator of pluripotency in vitro [80,81].”
• The Hippo pathway: regulators and regulations. (2013, background): “YAP and TAZ are required for the maintenance of mouse and human embryonic stem cell pluripotency, respectively (Varelas et al. 2008; Alarcon et al. 2009; Lian et al. 2010; Qin et al. 2012).”
• Transcriptional Addiction in Cancer (2017, neutral): “However, following their initial activation, these phosphorylated Smads are recognized by specific ubiquitin ligases operating in the nucleus, leading to their proteasome-mediated destruction (Alarcon et al., 2009).”
• Mechanisms and pathways of growth failure in primordial dwarfism. (2011, background): “For instance, Wnt, TGF-b, Sonic Hedgehog (Shh), and Notch all impact on Hippo pathway activity (Alarcon et al. 2009; Varelas et al. 2010; Zhao et al. 2010; Heallen et al. 2011).”