Department of Genetics, Ribeirão Preto Medical School, São Paulo University, Ribeirão Preto, São Paulo 14049-900, Brazil.
Department of Biofunctional, Center of Higher Education Morgana Potrich Eireli, Morgana Potrich College, Mineiros, Goiás 75830-000, Brazil.
Int J Mol Sci. 2018 Nov 20;19(11):3654. doi: 10.3390/ijms19113654.
Signaling pathways are highly diverse in filamentous fungi, allowing the cells to receive and process ambient information. Interaction of components from different pathways results in signaling networks. The mitogen-activated protein kinase (MAPK) pathway is dependent on phosphorylation that is accomplished by kinase proteins. Thus, the STE/PAK protein kinase family plays essential roles in MAPK signal transduction, regulating several cellular functions. The STE/PAK protein displays an autoinhibitory (Cdc42/Rac interactive binding-CRIB) domain on its N-terminal portion, which interacts with the C-terminal catalytic kinase domain. Based on current knowledge, for the STE/PAK kinase to be activated, molecular signals (e.g., interaction with the activated form of Rac1 and Cdc42 proteins) or proteolytic cleavage by caspase 3 is necessary. Both mechanisms release the kinase domain from the CRIB interaction. Here, we hypothesize a novel molecular mechanism for the activation of STE20/PAKA kinase in based on an alternative pre-mRNA splicing process. Our data suggest that, because of the retention of intron 1 of this gene, it is theoretically possible that the translation of STE20/PAKA kinase will be free of its autoinhibitory CRIB domain. These findings indicate a rapid response system to environmental changes. Furthermore, STE20/PAKA may be a potential virulence factor and an interesting target for new drugs against dermatophytes.
信号通路在丝状真菌中高度多样化，使细胞能够接收和处理环境信息。不同途径的成分相互作用会产生信号网络。丝裂原活化蛋白激酶 (MAPK) 途径依赖于激酶蛋白完成的磷酸化。因此，STE/PAK 蛋白激酶家族在 MAPK 信号转导中发挥着重要作用，调节着几种细胞功能。STE/PAK 蛋白在其 N 端部分显示出自动抑制（CDC42/Rac 相互作用结合-CRIB）结构域，该结构域与 C 端催化激酶结构域相互作用。根据目前的知识，为了使 STE/PAK 激酶被激活，需要分子信号（例如，与 Rac1 和 Cdc42 蛋白的激活形式相互作用）或 caspase 3 的蛋白水解切割。这两种机制都使激酶结构域脱离 CRIB 相互作用。在这里，我们基于一个替代的前体 mRNA 剪接过程，提出了一种关于 STE20/PAKA 激酶在中的激活的新分子机制。我们的数据表明，由于该基因的内含子 1被保留，从理论上讲，STE20/PAKA 激酶的翻译将不再受到其自动抑制 CRIB 结构域的影响。这些发现表明了一种对环境变化的快速反应系统。此外，STE20/PAKA 可能是一种潜在的 毒力因子，也是针对皮肤真菌病新药的一个有趣靶点。
