Bionos Biotech SL; Biopolo Hospital La Fe, Valencia, Spain.
Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
Oncogene. 2023 May;42(21):1741-1750. doi: 10.1038/s41388-023-02672-z. Epub 2023 Apr 8.
KRAS, HRAS and NRAS proto-oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS proteins consist of a globular G-domain (aa1-166) and a 22-23 aa unstructured hypervariable region (HVR) that mediates membrane targeting. The evolutionary origins of the RAS isoforms, their HVRs and alternative splicing of the KRAS locus has not been explored. We found that KRAS is basal to the RAS proto-oncogene family and its duplication generated HRAS in the common ancestor of vertebrates. In a second round of duplication HRAS generated NRAS and KRAS generated an additional RAS gene we have designated KRASBL, absent in mammals and birds. KRAS4A arose through a duplication and insertion of the 4 exon of NRAS into the 3 intron of KRAS. We found evolutionary conservation of a short polybasic region (PBR1) in HRAS, NRAS and KRAS4A, a second polybasic region (PBR2) in KRAS4A, two neutralized basic residues (NB) and a serine in KRAS4B and KRASBL, and a modification of the CaaX motif in vertebrates with farnesyl rather than geranylgeranyl polyisoprene lipids, suggesting that a less hydrophobic membrane anchor is critical to RAS protein function. The persistence of four RAS isoforms through >400 million years of evolution argues strongly for differential function.
KRAS、HRAS 和 NRAS 原癌基因属于一个具有 40 个高度同源基因的家族，而这些基因又属于编码小 GTP 酶的 >160 个基因超家族的一个子集。RAS 蛋白由一个球形的 G 结构域（aa1-166）和一个 22-23 个氨基酸的无规则超变区（HVR）组成，该 HVR 介导膜靶向。RAS 同工型、其 HVR 和 KRAS 基因座的选择性剪接的进化起源尚未得到探索。我们发现 KRAS 是 RAS 原癌基因家族的基础，其在脊椎动物的共同祖先中产生了 HRAS。在第二轮复制中，HRAS 产生了 NRAS，而 KRAS 则产生了我们命名为 KRASBL 的另一个 RAS 基因，该基因在哺乳动物和鸟类中不存在。KRAS4A 是通过 NRAS 的 4 个外显子插入 KRAS 的 3 个内含子而产生的。我们发现 HRAS、NRAS 和 KRAS4A 中短多碱性区（PBR1）、KRAS4A 中的第二个多碱性区（PBR2）、KRAS4B 和 KRASBL 中的两个中和碱性残基（NB）和丝氨酸、以及脊椎动物中 CaaX 基序的修饰具有法呢基而不是香叶基香叶基多异戊二烯脂质，这表明 RAS 蛋白功能对疏水性较弱的膜锚定至关重要。四个 RAS 同工型在超过 4 亿年的进化过程中得以保留，这强烈支持了它们具有不同的功能。
