Sträng Jan Eric, Schuler Rainer, Kühl Michael, Kestler Hans A
Institute of Medical Systems Biology, Ulm University, 89081 Ulm, Germany.
Institute of Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany.
J Theor Biol. 2017 Sep 21;429:82-94. doi: 10.1016/j.jtbi.2017.06.027. Epub 2017 Jun 23.
Wnt signaling plays a role in diverse processes such as cell proliferation, differentiation, migration or cell polarity. Dysfunction of Wnt signaling is associated with human diseases and aging. Wnts can activate several interacting intracellular signaling pathways, in particular the so called canonical and non-canonical pathways. The canonical Wnt response leads to a stabilization of cytoplasmic β-catenin whereas non-canonical Wnt signaling can result in the activation of calcium-calmodulin dependent kinase II (CamKII). Earlier data revealed that those signaling pathways can inhibit each other in a concentration dependent manner. During Xenopus laevis dorsal axis formation, Wnt11 has been shown to activate both, β-catenin signaling as well as CamKII activity. In line, Wnt11 is required for dorsal as well as ventral cell fates. Here, we show that the concentration dependent mutual inhibition of CamKII and β-catenin signaling is sufficient to obtain a switch-like behavior as opposed to a graded response. We present a model that faithfully recapitulates the activity of Wnt11 during dorso-ventral axis formation in Xenopus laevis on the basis of the Wnt switch behavior.
Wnt信号传导在多种过程中发挥作用,如细胞增殖、分化、迁移或细胞极性。Wnt信号传导功能障碍与人类疾病和衰老相关。Wnts可激活多种相互作用的细胞内信号通路,特别是所谓的经典和非经典通路。经典Wnt反应导致细胞质β-连环蛋白稳定,而非经典Wnt信号传导可导致钙调蛋白依赖性激酶II(CamKII)激活。早期数据显示,这些信号通路可在浓度依赖性方式下相互抑制。在非洲爪蟾背轴形成过程中,Wnt11已被证明可激活β-连环蛋白信号传导以及CamKII活性。同样,背侧和腹侧细胞命运都需要Wnt11。在此,我们表明,与分级反应相反,CamKII和β-连环蛋白信号传导的浓度依赖性相互抑制足以获得类似开关的行为。我们提出了一个模型,该模型基于Wnt开关行为忠实地再现了非洲爪蟾背腹轴形成过程中Wnt11的活性。