AKT 抑制 TSC 复合物形成的作用
中文名称
通路描述
tuberous sclerosis complex (TSC) 是一种多系统遗传性疾病，由 TSC1 或 TSC2 肿瘤抑制基因的功能丧失突变引起，这两个基因形成的 TSC 复合物（TSC1-TSC2、TSC1:TSC2 或 hamartin-tuberin 复合物）负责调节 mTORC1 活性。TSC 复合物作为 RHEB 小 GTPase 的 GTPase 激活蛋白（GAP），将激活 mTORC1 的 GTP 结合型 RHEB 转化为无活性的 GDP 结合型形式，从而抑制 mTORC1 的激活。AKT（PKB）对 TSC2 的多位点磷酸化可解除 TSC 复合物对 RHEB 的抑制作用。AKT 介导的 TSC2 磷酸化至少以两种方式影响 TSC2 功能：首先，磷酸化降低 TSC2 活性；其次，磷酸化使 TSC2 蛋白不稳定，通过破坏 TSC1 与 TSC2 之间的复合物形成并诱导游离 TSC2 的泛素化来实现。此外，TSC 复合物还通过调节一个负反馈回路发挥作用，该回路中 mTORC1 激活的 S6K1（RPS6KB1）抑制胰岛素介导的 PI3K/AKT 信号传导，并在某些癌症类型中促进肿瘤发生。
英文描述
ASS1 variants cause citrullinemia Argininosuccinate synthase (ASS1) plays a critical role in the detoxification of ammonia, catalyzing the third step of the urea cycle, the ATP-dependent condensation of citrulline and aspartate to yield argininosuccinate (Diez-Fernandez et al, 2016; Shaheen et al, 1994; Berning et al, 2008). ASS1 is a cytosolic enzyme that is expressed at highest levels in hepatocytes, but is also expressed in the kidney at lower levels.
Mutations in ASS1 cause type 1 citrullinemia (OMIM 215700), an autosomal recessive inborn error of metabolism affecting ~ 1 in 250,000 live births (Posset et al, 2020; reviewed in Quinonez and Lee, 2022). Like other urea cycle disorders (UCDs), citrullinemia is characterized by hyperammonemia. Enzyme deficiency is also associated with high plasma levels of citrulline, glutamine, and orotic acid, with low arginine. Severe cases of citrullinemia result in encephalopathy, characterized by lethargy, vomiting, seizures, coma and death (reviewed in Matsumoto eta al, 2019; Schmitt Ribas et al, 2022; Quinonez and Lee, 2022).
Over 100 distinct disease-causing variants have been cataloged, including missense, nonsense, splice-site, deletions, and frameshift mutations (Diez-Fernandez et al, 2017). While some variants are identified in multiple cases, such as the most common allele G390R, others are private. Missense mutations typically disrupt enzyme folding or activeâsite interactions (citrulline/aspartate binding), reducing catalytic activity.
Nonsense, frameshift, or splicing variants can truncate the protein or eliminate key exons, resulting in non-functional or absent enzyme (reviewed in Quinonez and Lee, 2022).
Mutations in ASS1 cause type 1 citrullinemia (OMIM 215700), an autosomal recessive inborn error of metabolism affecting ~ 1 in 250,000 live births (Posset et al, 2020; reviewed in Quinonez and Lee, 2022). Like other urea cycle disorders (UCDs), citrullinemia is characterized by hyperammonemia. Enzyme deficiency is also associated with high plasma levels of citrulline, glutamine, and orotic acid, with low arginine. Severe cases of citrullinemia result in encephalopathy, characterized by lethargy, vomiting, seizures, coma and death (reviewed in Matsumoto eta al, 2019; Schmitt Ribas et al, 2022; Quinonez and Lee, 2022).
Over 100 distinct disease-causing variants have been cataloged, including missense, nonsense, splice-site, deletions, and frameshift mutations (Diez-Fernandez et al, 2017). While some variants are identified in multiple cases, such as the most common allele G390R, others are private. Missense mutations typically disrupt enzyme folding or activeâsite interactions (citrulline/aspartate binding), reducing catalytic activity.
Nonsense, frameshift, or splicing variants can truncate the protein or eliminate key exons, resulting in non-functional or absent enzyme (reviewed in Quinonez and Lee, 2022).
所含基因
1 个基因