Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA.
Semin Cancer Biol. 2019 Feb;54:109-113. doi: 10.1016/j.semcancer.2018.02.009. Epub 2018 Feb 27.
Ras signaling initiates at the plasma membrane. Thus, Ras behavior at the membrane and how it relates to its interactions with Raf and PI3Kα, are of immense interest. Here we review factors influencing Ras lateral diffusion. We then ask whether oncogenic Ras diffusion speed in the membrane is important for signaling response times and whether it affects ubiquitously all pathways. We suggest that if Ras expression is sufficiently high to dimerize (or form nanoclusters), signaling response of those pathways where dimers (or nanoclusters) are involved corresponds to the speed with which Ras molecules travel in the membrane. On average, the faster the rate at which Ras travels to dimerize, the shorter the time to MAPK signaling; but not PI3Kα. However, we argue that KRas speed may not play an important functional role because changes in mobility at this scale are unlikely to be significant. In line with this, despite the anchors' variability, lateral diffusion speeds of KRas and HRas are similar, as is that of Lck kinase; however, even though with similar anchor, Cdc42 mobility presents a different pattern, commensurate with its role in the positioning of the apical domain, suggesting that mobility evolved for function.
Ras 信号起始于质膜。因此，Ras 在膜上的行为及其与 Raf 和 PI3Kα 的相互作用方式引起了广泛的关注。本文综述了影响 Ras 侧向扩散的因素。然后，我们提出以下问题：致癌 Ras 在膜中的扩散速度是否对信号转导的响应时间很重要，以及它是否会影响所有途径。我们认为，如果 Ras 的表达水平足够高，足以形成二聚体（或纳米簇），那么涉及二聚体（或纳米簇）的这些途径的信号转导响应与 Ras 分子在膜中移动的速度相对应。平均而言，Ras 二聚化的速度越快，MAPK 信号的时间就越短；但对 PI3Kα 则不然。然而，我们认为 KRas 的速度可能没有发挥重要的功能作用，因为在这个尺度上的迁移率变化不太可能是显著的。与这一观点一致的是，尽管锚定蛋白的变化，KRas 和 HRas 的侧向扩散速度相似，Lck 激酶也是如此；然而，尽管有类似的锚定蛋白，Cdc42 的迁移率呈现出不同的模式，与其在顶端域定位中的作用相一致，表明迁移率是为了功能而进化的。
