Yeast Physiology Group, Department of Genetics and Microbiology, Facultad de Biología, Universidad de Murcia, 30071 Murcia, Spain.
Sci Rep. 2016 Nov 23;6:37515. doi: 10.1038/srep37515.
In eukaryotic cells, the highly conserved Target of Rapamycin (TOR) and the Mitogen Activated Protein Kinase (MAPK) signaling pathways elicit adaptive responses to extra- and intracellular conditions by regulating essential cellular functions. However, the nature of the functional relationships between both pathways is not fully understood. In the fission yeast Schizosaccharomyces pombe the cell integrity MAPK pathway (CIP) regulates morphogenesis, cell wall structure and ionic homeostasis. We show that the Rab GTPase Ryh1, a TORC2 complex activator, cross-activates the CIP and its core member, the MAPK Pmk1, by two distinct mechanisms. The first one involves TORC2 and its downstream effector, Akt ortholog Gad8, which together with TORC1 target Psk1 increase protein levels of the PKC ortholog Pck2 during cell wall stress or glucose starvation. Also, Ryh1 activates Pmk1 in a TORC2-independent fashion by prompting plasma membrane trafficking and stabilization of upstream activators of the MAPK cascade, including PDK ortholog Ksg1 or Rho1 GEF Rgf1. Besides, stress-activated Pmk1 cross-inhibits Ryh1 signaling by decreasing the GTPase activation cycle, and this ensures cell growth during alterations in phosphoinositide metabolism. Our results reveal a highly intricate cross-regulatory relationship between both pathways that warrants adequate cell adaptation and survival in response to environmental changes.
在真核细胞中，高度保守的雷帕霉素靶蛋白（TOR）和丝裂原活化蛋白激酶（MAPK）信号通路通过调节基本的细胞功能，对细胞外和细胞内的条件产生适应性反应。然而，这两条通路之间功能关系的性质尚不完全清楚。在裂殖酵母 Schizosaccharomyces pombe 中，细胞完整性 MAPK 通路（CIP）调节形态发生、细胞壁结构和离子动态平衡。我们表明，Rab GTPase Ryh1 是 TORC2 复合物的激活剂，通过两种不同的机制交叉激活 CIP 及其核心成员 MAPK Pmk1。第一种机制涉及 TORC2 和其下游效应物 Akt 同源物 Gad8，它们与 TORC1 一起靶向 Psk1，在细胞壁应激或葡萄糖饥饿时增加 PKC 同源物 Pck2 的蛋白水平。此外，Ryh1 通过促使质膜运输和稳定 MAPK 级联的上游激活物，包括 PDK 同源物 Ksg1 或 Rho1 GEF Rgf1，以 TORC2 非依赖性的方式激活 Pmk1。此外，应激激活的 Pmk1 通过降低 GTPase 激活循环来交叉抑制 Ryh1 信号，这确保了在磷酸肌醇代谢改变时细胞的生长。我们的结果揭示了这两条通路之间高度复杂的交叉调节关系，这保证了细胞在应对环境变化时进行适当的适应和存活。
