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. 2021 Jul 22;11:14931. doi: 10.1038/s41598-021-94393-0

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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 network including transcription factors CREB1/2, regulated by PKA and MAPK signaling pathways. (A) Complete pathways in the extended model. The pathways from Fig. 3A are represented as solid, thinner, lines, and the pathway numbers are indicated with unfilled circles. The newly added pathways are dashed, thicker lines, and pathway numbers are indicated with filled circles. The PKA and MAPK cascades interact to regulate the phosphorylation and activities of CREB1 and CREB2, which regulate the expression of TBL. TBL subsequently activates TGF-β. Violet denotes two ERK – > TBL pathways: ERK- > RSK- > CREB1- > TBL, pathway 7- > 16- > 19); ERK- > CREB2- > TBL, pathway 17- > 20). Arrowheads indicate activation, circular ends indicate repression. (B) Network highlighting the addition of new pathways, with the previous pathways made transparent.