Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways

Abstract

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.

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

“…The expression of PSs 1, 5, and 8, which are specifically induced by BMPs and no other TGFβ family members [29], was found in a large number of cells within the endoneurium. Not only was the expression in many more cells than in the mouse model, normal nerves from patients not suffering from HO were totally negative.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Such a difference in TAZ and YAP requirement by human and mouse ESCs might be explained by the differential requirement of TGFbeta or bone morphogenetic protein (BMP) signaling by human and mouse ESCs respectively. TAZ was shown to promote Smad2/3 nuclear localization in response to TGFbeta signaling and YAP was demonstrated to support Smad1-dependent transcription under BMP signaling (Varelas et al, 2008;Alarcón et al, 2009). However, the mechanism responsible for specificity of YAP and TAZ in BMP and TGFbeta signaling is not known.…”

When pathways collide: collaboration and connivance among signalling proteins in development

“…A recent study revealed that YAP can act as a transcriptional activator in the bone morphogenic protein (BMP) pathway with Smad1, and is needed for BMP suppression of neural differentiation of mouse embryonic stem cells 79 . Therefore when Hippo pathway activity is high, YAP is phosphorylated and excluded from the nucleus, reducing activity of the BMP pathway.…”

“…This provides integration of Hippo and BMP signaling at the transcriptional level. This integration is conserved, as in Drosophila, Yorkie is needed for maximal signaling by the BMP ortholog Decapentaplegic (Dpp) 79 . Recent studies have revealed that YAP also provides an integration point in Hedgehog signaling 80 , acting as a transcriptional coactivator for Gli transcription factors.…”