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. 2021 Feb 11;11:3588. doi: 10.1038/s41598-021-82954-2

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Schematic of Smad4 regulation of cardiac-specific gene expression and nuclear localization of Nkx2-5. Bmp activates its receptor, which then phosphorylates the Smad1/5/8 complex. In turn, the Smad1/5/8 complex binds to Smad4, which subsequently translocates into the nucleus to enhance Nkx2-5 transcription. Nkx2-5 protein is phosphorylated by CK2 and forms a protein complex with Smad4. This complex translocates into the nucleus and regulates Nkx2-5 transcription, thereby maintaining Nkx2-5 expression. Through this mechanism, Smad4 plays a decisive role in cardiac development and myocardial differentiation.