Ral 通过一个在 C. elegans 细胞命运模式中的 MAP4 激酶-p38 MAP 激酶级联信号传导。
Ral Signals through a MAP4 Kinase-p38 MAP Kinase Cascade in C. elegans Cell Fate Patterning.
机构信息
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
出版信息
Cell Rep. 2018 Sep 4;24(10):2669-2681.e5. doi: 10.1016/j.celrep.2018.08.011.
C. elegans vulval precursor cell (VPC) fates are patterned by an epidermal growth factor (EGF) gradient. High-dose EGF induces 1° VPC fate, and lower dose EGF contributes to 2° fate in support of LIN-12/Notch. We previously showed that the EGF 2°-promoting signal is mediated by LET-60/Ras switching effectors, from the canonical Raf-MEK-ERK mitogen-activated protein (MAP) kinase cascade that promotes 1° fate to the non-canonical RalGEF-Ral that promotes 2° fate. Of oncogenic Ras effectors, RalGEF-Ral is by far the least well understood. We use genetic analysis to identify an effector cascade downstream of C. elegans RAL-1/Ral, starting with an established Ral binding partner, Exo84 of the exocyst complex. Additionally, RAL-1 signals through GCK-2, a citron-N-terminal-homology-domain-containing MAP4 kinase, and PMK-1/p38 MAP kinase cascade to promote 2° fate. Our study delineates a Ral-dependent developmental signaling cascade in vivo, thus providing the mechanism by which lower EGF dose is transduced.
秀丽隐杆线虫的表皮生长因子 (EGF) 梯度决定了其生殖前体细胞 (VPC) 的命运。高剂量的 EGF 诱导 1° VPC 命运，而较低剂量的 EGF 则有助于支持 LIN-12/Notch 的 2°命运。我们之前曾表明，EGF 促进 2°命运的信号是由 LET-60/Ras 开关效应物介导的，从促进 1°命运的经典 Raf-MEK-ERK 丝裂原激活蛋白 (MAP) 激酶级联反应到促进 2°命运的非经典 RalGEF-Ral。在致癌性 Ras 效应物中，RalGEF-Ral 是迄今为止了解最少的。我们使用遗传分析来鉴定秀丽隐杆线虫 RAL-1/Ral 下游的效应物级联反应，从外泌体复合物的已建立的 Ral 结合伴侣 Exo84 开始。此外，RAL-1 通过 GCK-2（一种含有 citron-N 端同源结构域的 MAP4 激酶）和 PMK-1/p38 MAP 激酶级联反应传递信号，以促进 2°命运。我们的研究描绘了一个 Ral 依赖性的体内发育信号级联反应，从而提供了低剂量 EGF 转导的机制。
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