Program in Epithelial Biology, Stanford University, Stanford, CA, 94305, USA.
Program in Cancer Biology, Stanford University, Stanford, CA, 94305, USA.
Nat Commun. 2019 Nov 11;10(1):5118. doi: 10.1038/s41467-019-13106-4.
KRAS receives and relays signals at the plasma membrane (PM) where it transmits extracellular growth factor signals to downstream effectors. SNORD50A/B were recently found to bind KRAS and inhibit its tumorigenic action by unknown mechanisms. KRAS proximity protein labeling was therefore undertaken in SNORD50A/B wild-type and knockout cells, revealing that SNORD50A/B RNAs shape the composition of proteins proximal to KRAS, notably by inhibiting KRAS proximity to the SNARE vesicular transport proteins SNAP23, SNAP29, and VAMP3. To remain enriched on the PM, KRAS undergoes cycles of endocytosis, solubilization, and vesicular transport to the PM. Here we report that SNAREs are essential for the final step of this process, with KRAS localization to the PM facilitated by SNAREs but antagonized by SNORD50A/B. Antagonism between SNORD50A/B RNAs and specific SNARE proteins thus controls KRAS localization, signaling, and tumorigenesis, and disrupting SNARE-enabled KRAS function represents a potential therapeutic opportunity in KRAS-driven cancer.
KRAS 在质膜 (PM) 接收和传递信号，在那里它将细胞外生长因子信号传递到下游效应物。最近发现 SNORD50A/B 与 KRAS 结合，并通过未知机制抑制其致癌作用。因此，在 SNORD50A/B 野生型和敲除细胞中进行了 KRAS 邻近蛋白标记，结果表明 SNORD50A/B RNA 塑造了 KRAS 邻近蛋白的组成，特别是通过抑制 KRAS 与 SNARE 囊泡运输蛋白 SNAP23、SNAP29 和 VAMP3 的接近。为了保持在 PM 上的富集，KRAS 经历内吞、溶解和囊泡运输到 PM 的循环。在这里，我们报告说 SNARE 对于这个过程的最后一步是必不可少的，KRAS 定位于 PM 是由 SNARE 介导的，但被 SNORD50A/B 拮抗。因此，SNORD50A/B RNA 与特定 SNARE 蛋白之间的拮抗作用控制 KRAS 的定位、信号转导和致癌作用，破坏 SNARE 介导的 KRAS 功能代表了 KRAS 驱动的癌症中的一个潜在治疗机会。
