KRAS
小结
KRAS是致癌基因，编码蛋白是一种GTP酶，是小型GTP酶RAS家族的成员，RAS家族催化GTP水解为GDP。在生理条件下，这些RAS蛋白在活性（GTP结合）和非活性（GDP结合）状态之间循环，以激活受体酪氨酸激酶（RTK）下游的MAPK和PI3K致癌途径信号传导。RAS酶的功能受鸟嘌呤核苷酸交换因子（GEF）如SOS的调节，这些因子可以使GDP与GTP交换，也可以通过GTP酶活化蛋白如NF1调节，从而提高RAS水解GTP的能力 。一旦被激活，RAS通过激活不同的细胞内信号传导途径（包括RAF / MEK / ERK和PI3K / AKT / mTOR途径）介导细胞增殖和其他细胞功能的调节。KRAS中激活突变常见于胰腺癌，结肠癌，子宫内膜癌，卵巢癌和胆管癌；几乎所有这些突变都导致KRAS的组成型活化，从而促进细胞增殖。KRAS突变热点为G12，G13和Q61，前两个发生在GTP-ase结构域，后者干扰NF1结合和调节KRAS的能力。KRAS胚系突变导致Noonan综合征（NS）和心脏-面部-皮肤（CFC）综合征。
KRAS is a member of the RAS family of small GTPases, which catalyze the hydrolysis of GTP to GDP. Under physiologic conditions, these RAS proteins cycle between an active (GTP-bound) and an inactive (GDP-bound) state, to activate the MAPK and PI3K oncogenic pathway signaling downstream of Receptor Tyrosine Kinases (RTKs). The function of RAS enzymes is regulated by guanine nucleotide exchange factors (GEFs), such as SOS, which enable the exchange of GDP to GTP, as well as by GTPase activating proteins, such as NF1, which increase the ability of RAS to hydrolyze GTP. Once activated, RAS mediates the regulation of cellular proliferation and other cellular functions through the activation of distinct intracellular signaling pathways, including the RAF/MEK/ERK and PI3K/AKT/mTOR pathways. Transforming mutations in KRAS are frequently found in pancreatic, colon, endometrial, ovarian and biliary cancers; almost all of these mutations result in constitutive activation of KRAS, thereby promoting cell proliferation. KRAS mutations occur primarily in three major hotspots, G12, G13 and Q61, the first two of which occur in the GTP-ase domain and the latter interferes with the ability of NF1 to bind and regulate KRAS. Other less well-characterized mutations such as A146T/V/P and L19F have also been characterized and found to be activating albeit at lower frequencies. Germline KRAS mutations are responsible for both Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome that are associated with hyperactivated MAPK pathway, distinctive clinical characteristics and a predisposition to cancer.