Components, dynamics and effectors of the MAK2 MAP kinase cascade

背景：微生物之间的交流是一个基本的生物学问题。丝状真菌分泌大量的代谢产物和推定的信号分子是解决这个问题的极好的模型系统。化学梯度感应和细胞极性调节之间的联系在任何真核系统中都知之甚少。在粗糙脉孢菌中，一种未知的化学配体介导趋化性相互作用，导致基因相同的细胞融合。这种自我信号传导的过程是基于MAK2 MAP激酶级联向通信细胞的相对尖端的振荡募集。归巢细胞的这两种不同生理状态的快速交替可能反映了信号传递和响应。目的：我们对振荡MAK2信号传导机制的理解受到以下事实的阻碍：信号传导机制的大多数组分，包括假定的分泌信号及其同源受体、MAP激酶级联的调节剂以及MAK2靶点，都是未知的。该研究项目的长期目标是了解脉动MAK2信号传导的机制。该提案的具体目标是（i）定义MAK2级联的组成部分，动力学和调节，以及（ii）表征指导化能营养生长反应的MAK2途径效应物。重要性：菌丝融合类似于高等真核生物中遗传上相同的细胞之间的细胞融合，其结果是形成多核合胞体。人类生物学的重要例子是肌肉分化过程中的成肌细胞融合，胎盘发育过程中的滋养层融合和骨形成过程中的破骨细胞融合。因此，真菌自我信号提供了一个有用的模型，了解更复杂的生物体中的细胞通讯的分子机制。此外，细胞间通讯和体细胞融合通过共享单个细胞的营养和细胞器对真菌菌落的建立和功能起重要作用。因此，菌丝融合对于病原真菌的宿主定殖和毒力也是至关重要的。了解这一过程将对我们干预这一过程的能力产生重大影响，无论是在有害真菌的情况下抑制它，还是在需要有益生长时增强它。

Background: Communication among microbes is a fundamental biological problem. Filamentous fungi that secrete a vast array of metabolites and putative signaling molecules are excellent model systems to address this problem. The connection between chemical gradient sensing and regulation of cell polarity is only poorly understood in any eukaryotic system. In Neurospora crassa an unknown chemical ligand mediates chemotropic interactions resulting in cell fusion of genetically identical cells. This process of self-signaling is based on the oscillatory recruitment of the MAK2 MAP kinase cascade to the opposing tips of communicating cells. The rapid alternation of these two different physiological states of homing cells likely reflects signal delivery and response. Objectives: Our mechanistic understanding of oscillatory MAK2 signaling is hampered by the fact that most components of the signaling machinery, including a postulated secreted signal and its cognate receptor, regulators of the MAP kinase cascade as well as MAK2 targets, are unknown. The long-term goal of this research project is the mechanistic understanding of pulsatile MAK2 signaling. The specific objectives for the proposal are (i) defining components, dynamics and regulation of the MAK2 cascade, and (ii) characterizing MAK2 pathway effectors that guide the chemotrophic growth response. Significance: Hyphal fusion is comparable to cell fusion between genetically identical cells of higher eukaryotes, which results in the formation of multinuclear syncytia. Important examples for human biology are myoblast fusion during muscle differentiation, trophoblast fusion during placental development and osteoclast fusion during bone formation. Thus, fungal self-signaling provides a useful model for understanding molecular mechanisms of cell communication in more complex organisms. Moreover, intercellular communication and somatic cell fusion is important for establishment and function of the fungal colony by sharing nutrients and organelles of individual cells. Hyphal anastomosis is thus also critical for host colonization and virulence of pathogenic fungi. Understanding this process will have significant implications on our ability to intervene in this process by either inhibiting it in cases of detrimental fungi or enhancing it when beneficial growth is desired.