ERBB2 突变体介导的信号通路
中文名称
通路描述
ERBB2 激酶结构域（KD）的突变导致其持续激活，促进与 EGFR 家族其他成员形成异二聚体，并增强信号强度，从而引起细胞转化（Kancha et al. 2011）。目前仅测试了部分潜在异二聚化伙伴，因此注释有限。ERBB2 L755S 和 ERBB2 V777L 癌变体在更高速率下与 ERBB3（HER3）形成异二聚体（Croessmann et al. 2019）。ERBB2 L755S、L755P、V777L、D769H、D769Y、V842I、R896C 和 G778_P780dup 在 EGFR（Kancha et al. 2011, Bose et al. 2013）或 ERBB3（Kancha et al. 2011, Bose et al. 2013, Collier et al. 2013）作为异二聚化伙伴存在时显示出增强的活性。ERBB2 G778_P780dup、I767M 和 R896C 与 ERBB3 的相互作用尚未测试。ERBB2 L869R 在存在 ERBB3 时活性增加，且在存在促进二聚化的 ERBB3 E928G 突变体时进一步增强（Hanker et al. 2017）。ERBB2 L869R 与 EGFR 的相互作用尚未测试。ERBB2 KD 突变体与 ERBB4 的异二聚化尚未测试，但 ERBB4 是这些 KD 变体的潜在异二聚化伙伴。ERBB2 H878Y 突变体的激酶活性比野生型 ERBB2 高 10 倍（Hu, Wan et al. 2015; Hu, Hu et al. 2015），但其异二聚化特性尚未研究，因此标注为候选。未研究 ERBB2 KD 突变体异二聚化中的配体需求，但假设配体是必需的。ERBB2 L755M（Gonzalez-Alonso et al. 2015）、L755W（COSMIC 数据库：Forbes et al. 2017）、V777E（Dietz et al. 2017）、V777M（Lee et al. 2006, Ross et al. 2016, Zehir et al. 2017）、D769N（Tschui et al. 2015）、V842E（Siroy et al. 2015）、R896H（Cancer Genome Atlas Research Network 2011）、L869Q（Lee et al. 2006）和 H878R（Trowe et al. 2008, Zehir et al. 2017）的表观特性尚未通过实验测试，但根据 COSMIC 数据库（Forbes et al. 2017）预测其具有致病性，并标注为候选。T733I 和 T798I 通常作为 ERBB2 的次要突变发生，与治疗失败相关。单独来看，ERBB2 T733I 和 T798I 的转化能力弱于其他 ERBB2 KD 突变体。由于其表观特性研究不足，ERBB2 T733I、T798I 和 T798M 标注为候选。ERBB2 KD 突变体与 ERBIN 和 HSP90:CDC37 共伴侣复合物的结合尚未测试，但假设其发生机制与野生型 ERBB2 类似。ERBB2 KD 突变体的信号通路已根据这些突变体的生物学知识（异二聚化、下游信号、药物相互作用）以及其突变体的序列相似性进行了组织。
英文描述
Formation of the dystrophin-glycoprotein complex (DGC) The dystrophin-glycoprotein complex (DGC, also known as DAPC, dystrophin associated protein complex) is a large, multimeric complex of proteins and glycoproteins localized near the plasma membrane that connects the intracellular cell cytoskeleton with the extracellular matrix and laminins (reviewed in Bhat et al, 2018). In muscle cells, the DGC plays roles in stabilizing the sarcolemma and transducing mechanical stimuli (reviewed in Wilson et al, 2022), but DGC complexes are found in several other cell types and tissues and play more general roles in membrane stability, signal transduction and organization of ion channels and GABA channels (reviewed in Waite et al, 2012; Gawor and PrózyÅski, 2018; Bhat et al, 2018). While mutations in some components of the DGC are reported to make muscle fibers more susceptible to damage and lead to various types of muscle disorder such as Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophies and cardiomyophathies (Straub and Campbell, 1997; Cohn and Campbell, 2000), DGC components have also been associated with disorders in non-muscle tissue (Gumerson and Michele, 2011).
The core of the DGC is made up of DAG1 (dystroglycan), DMD (dystrophin) and Utrophin. DAG1 is present as a non-covalently associated alpha and beta chain following cleavage at serine 654. Extracellular alpha-DAG1 (30-653) contacts the extracellular matrix by virtue of interactions between the O-linked glycosyl groups and laminins, while the transmembrane beta-DAG1(684-895) interacts with the cytosolic dystrophin protein DMD.
The DGC also consists of a transmembrane sarcoglycan complex consisting of four sarcoglycan (SGC) proteins and SSPN (sarcospan). On the intracelluar side, DMD and beta-DAG1 recruit membrane-associated cytosolic proteins including members of the dystrobrevin (DTN) and syntrophin (SNT) families (reviewed in Bhat et al, 2018).
The core of the DGC is made up of DAG1 (dystroglycan), DMD (dystrophin) and Utrophin. DAG1 is present as a non-covalently associated alpha and beta chain following cleavage at serine 654. Extracellular alpha-DAG1 (30-653) contacts the extracellular matrix by virtue of interactions between the O-linked glycosyl groups and laminins, while the transmembrane beta-DAG1(684-895) interacts with the cytosolic dystrophin protein DMD.
The DGC also consists of a transmembrane sarcoglycan complex consisting of four sarcoglycan (SGC) proteins and SSPN (sarcospan). On the intracelluar side, DMD and beta-DAG1 recruit membrane-associated cytosolic proteins including members of the dystrobrevin (DTN) and syntrophin (SNT) families (reviewed in Bhat et al, 2018).
所含基因
36 个基因