ERK and Akt exhibit distinct signaling responses following stimulation by pro-angiogenic factors

Song and Finley Cell Communication and Signaling https://doi.org/10.1186/s12964-020-00595-w (2020) 18:114 RESEARCH Open Access ERK and Akt exhibit distinct signaling responses following stimulation by proangiogenic factors Min Song1 and Stacey D. Finley1,2,3* Abstract Background: Angiogenesis plays an important role in the survival of tissues, as blood vessels provide oxygen and nutrients required by the resident cells. Thus, targeting angiogenesis is a prominent strategy in many different settings, including both tissue engineering and cancer treatment. However, not all of the approaches that modulate angiogenesis lead to successful outcomes. Angiogenesis-based therapies primarily target pro-angiogenic factors such as vascular endothelial growth factor-A (VEGF) or fibroblast growth factor (FGF) in isolation, and there is a limited understanding of how these promoters combine together to stimulate angiogenesis. Targeting one pathway could be insufficient, as alternative pathways may compensate, diminishing the overall effect of the treatment strategy. Methods: To gain mechanistic insight and identify novel therapeutic strategies, we have developed a detailed mathematical model to quantitatively characterize the crosstalk of FGF and VEGF intracellular signaling. The model focuses on FGF- and VEGF-induced mitogen-activated protein kinase (MAPK) signaling to promote cell proliferation and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, which promotes cell survival and migration. We fit the model to published experimental datasets that measure phosphorylated extracellular regulated kinase (pERK) and Akt (pAkt) upon FGF or VEGF stimulation. We validate the model with separate sets of data. Results: We apply the trained and validated mathematical model to characterize the dynamics of pERK and pAkt in response to the mono- and co-stimulation by FGF and VEGF. The model predicts that for certain ranges of ligand concentrations, the maximum pERK level is more responsive to changes in ligand concentration compared to the maximum pAkt level. Also, the combination of FGF and VEGF indicates a greater effect in increasing the maximum pERK compared to the summation of individual effects, which is not seen for maximum pAkt levels. In addition, our model identifies the influential species and kinetic parameters that specifically modulate the pERK and pAkt responses, which represent potential targets for angiogenesis-based therapies. (Continued on next page) * Correspondence: 1 Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA 2 Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA Full list of author information is available at the end of the article © The Author(s). 2020 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Song and Finley Cell Communication and Signaling (2020) 18:114 Page 2 of 19 (Continued from previous page) Conclusions: Overall, the model predicts the combination effects of FGF and VEGF stimulation on ERK and Akt quantitatively and provides a framework to mechanistically explain experimental results and guide experimental design. Thus, this model can be utilized to study the effects of pro- and anti-angiogenic therapies that particularly target ERK and/or Akt activation upon stimulation with FGF and VEGF. Keywords: Computational modeling, Angiogenesis, Growth factor signaling, Sensitivity analysis Background Angiogenesis is the formation of new blood capillaries from pre-existing blood vessels. The essential role of blood vessels in delivering nutrients to tissues makes angiogenesis important in many different settings, including both physiological and pathological conditions. Physiologically, angiogenesis is involved in the growth of normal blood vessels during development such as placental vascularization during pregnancy [1, 2] and the wound healing process [3, 4]. Pathological angiogenesis is crucial in many diseases, including cancer [5]. Thus, targeting angiogenesis is a prominent strategy in many contexts, for example, in both tissue engineering and cancer treatment. In the context of tissue engineering, researchers have sought to create artificial tissues to substitute damaged tissues in response to a great shortage of donors for transplant surgery. Implementing strategies that promote the formation of adequate vasculature is critical for the long-term viability of engineered tissue constructs. Therefore, stimulating new blood vessel formation is an important strategy for tissue engineering [6]. On the other hand, inhibiting angiogenesis is a strategy for cancer treatment, as the formation of new blood vessels is important for cancer growth and metastasis. Therefore, understanding the angiogenesis process is very beneficial to current strategies that target vessel formation. Many different pro-angiogenic growth factors, such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), mediate angiogenesis [7, 8]. These factors promote different cellular processes involving endothelial cells leading to new blood vessel formation, including proliferation, migration, survival, and vessel maturation [9, 10]. Strategies to promote or inhibit angiogenesis focus on modulating the effects of the factors that promote these cellular-level processes. Unfortunately, not all approaches to promote or inhibit angiogenesis lead to successful outcomes. For example, clinical trials have shown no effective improvement in angiogenesis upon stimulation by FGF [11] or VEGF [12]. Also, bevacizumab, an antiangiogenic agent designed to sequester VEGF extracellularly, inhibiting VEGF-mediated signaling by preventing VEGF from binding to its receptor [13, 14], has limited effects in certain cancer types, and it is no longer approved for the treatment of metastatic breast cancer due t (...truncated)