The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells.
The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells.
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DOI：
10.1016/j.neo.2022.01.002
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Ouellette MM
中科院分区：
文献类型：
--
作者：
Palanivel C;Chaudhary N;Seshacharyulu P;Cox JL;Yan Y;Batra SK;Ouellette MM
Ras家族蛋白是控制增殖、存活和运动的膜结合GTP酶。许多形式的癌症是由RAS基因中的体细胞突变的获得驱动的。在胰腺癌（PC）中，超过90%的肿瘤在KRAS中携带激活突变。Ras信号通路组分的突变也可能是RASopathies（一组发育障碍）的原因。在RASopathies的一个子集中，致病突变是在LZTR 1蛋白中，LZTR 1蛋白是促进Ras蛋白降解的E3泛素连接酶的底物衔接子。在这里，我们表明，LZTR 1的功能是由糖原合成酶激酶3（GSK 3）。在PC细胞中，抑制或沉默GSK3导致Ras蛋白水平下降，包括野生型Ras蛋白和致癌Kras蛋白。这种下降伴随着Ras蛋白半衰期的3倍减少，并通过蛋白酶体的抑制或LZTR 1的敲除而被阻止。无论KRAS的突变状态如何，都观察到Ras蛋白的下降，并伴随着细胞增殖的丧失。这种增殖的损失被LZTR 1的敲低所阻断，并且可以通过KRAS或GSK 3的沉默来重现。这些结果揭示了一种新的GSK3调节的LZTR1依赖性机制，该机制控制Ras蛋白的稳定性和PC细胞的增殖。这一新途径的Ras信号转导的意义和其对GSK3抑制剂的治疗特性的贡献都进行了讨论。
Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated by the glycogen synthase kinase 3 (GSK3). In PC cells, inhibiting or silencing GSK3 led to a decline in the level of Ras proteins, including both wild type Ras proteins and the oncogenic Kras protein. This decline was accompanied by a 3-fold decrease in the half-life of Ras proteins and was blocked by the inhibition of the proteasome or the knockdown of LZTR1. Irrespective of the mutational status of KRAS, the decline in Ras proteins was observed and accompanied by a loss of cell proliferation. This loss of proliferation was blocked by the knockdown of LZTR1 and could be recapitulated by the silencing of either KRAS or GSK3. These results reveal a novel GSK3-regulated LZTR1-dependent mechanism that controls the stability of Ras proteins and proliferation of PC cells. The significance of this novel pathway to Ras signaling and its contribution to the therapeutic properties of GSK3 inhibitors are both discussed.
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影响因子：
5.7
作者：
Baumgart S;Chen NM;Zhang JS;Billadeau DD;Gaisina IN;Kozikowski AP;Singh SK;Fink D;Ströbel P;Klindt C;Zhang L;Bamlet WR;Koenig A;Hessmann E;Gress TM;Ellenrieder V;Neesse A
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