CBL 信号通路的调节
中文名称
通路描述
Cbl 是一种 E3 泛素 - 蛋白连接酶，通过靶向蛋白质进行泛素化和蛋白酶体降解来负向调节信号通路（Rao 等，2002）。Cbl 通过该机制负向调节 PI3K（Dufour 等，2008）。Cbl 与 PI3K p85 亚基的结合至少部分由酪氨酸磷酸化在 Y731 介导（Dufour 等，2008）。Fyn 和相关激酶 Hck 和 Lyn 已知与 Cbl 结合（Anderson 等，1997；Hunter 等，1999）。Fyn 被证明能够磷酸化 Cbl Y731（Hunter 等，1999）。Fyn 和 Cbl 的结合已被描述为构成性的（Hunter 等，1999）。CBL 进一步与 PI3K p85 亚基结合（Hartley 等，1995；Anderson 等，1997；Hunter 等，1997），这也描述为构成性的并由 p85 的 SH3 域介导。p85 SH2 域与 Cbl 上的特定磷酸化位点结合，据推测可解释在激活细胞中观察到的 Cbl/p85 结合增加（Panchamoorthy 等 1996），这负向调节 PI3K 活性（Fang 等，2001）。Cbl-PI3K 相互作用增加的负效应由 Cbl 的 Y731 介导。Cbl 结合增加 PI3K 泛素化和蛋白酶体降解（Dufour 等，2008）。
Cbl 在静止的造血细胞中与 Grb 构成性结合（Anderson 等，1997；Odai 等，1995；Park 等，1998；Panchamoorthy 等，1996）。Grb2 的 SH2 和 SH3 域均参与。Cbl 具有两个不同的 C 末端结构域：近端和远端。近端域在静止和激活的细胞中结合 Grb2，在激活的细胞中还与 Shc 结合。远端域结合调节蛋白 CRKL。Cbl 对 IL-3 的酪氨酸磷酸化释放 Grb2 的 SH3 域，然后该域游离以结合其他分子（Park 等，1998）。Cbl 对许多细胞因子如 IL-3、IL-2（Gesbert 等，1998）和 IL-4（Ueno 等，1998）的酪氨酸磷酸化。
Cbl 在静止的造血细胞中与 Grb 构成性结合（Anderson 等，1997；Odai 等，1995；Park 等，1998；Panchamoorthy 等，1996）。Grb2 的 SH2 和 SH3 域均参与。Cbl 具有两个不同的 C 末端结构域：近端和远端。近端域在静止和激活的细胞中结合 Grb2，在激活的细胞中还与 Shc 结合。远端域结合调节蛋白 CRKL。Cbl 对 IL-3 的酪氨酸磷酸化释放 Grb2 的 SH3 域，然后该域游离以结合其他分子（Park 等，1998）。Cbl 对许多细胞因子如 IL-3、IL-2（Gesbert 等，1998）和 IL-4（Ueno 等，1998）的酪氨酸磷酸化。
英文描述
Regulation of signaling by CBL Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl negatively regulates PI3K via this mechanism (Dufour et al. 2008). The binding of Cbl to the p85 subunit of PI3K is mediated at least in part by tyrosine phosphorylation at Y731 (Dufour et al. 2008). Fyn and the related kinases Hck and Lyn are known to be associated with Cbl (Anderson et al. 1997, Hunter et al. 1999). Fyn is proven capable of Cbl Y731 phosphorylation (Hunter et al. 1999).The association of Fyn and Cbl has been described as constitutive (Hunter et al. 1999). CBL further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this also described as constitutive and mediated by the SH3 domain of p85. Binding of the SH2 domain of p85 to a specific phosphorylation site in Cbl is postulated to explain the the increase in Cbl/p85 association seen in activated cells (Panchamoorthy et al 1996) which negatively regulates PI3K activity (Fang et al. 2001). The negative effect of increased Cbl-PI3K interaction is mediated by Y731 of Cbl. Cbl binding increases PI3K ubiquitination and proteasome degradation (Dufour et al. 2008).
Cbl is constitutively associated with Grb in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain binds the adaptor protein CRKL. Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). Cbl is tyrosine phosphorylated in response to many cytokines including IL-3, IL-2 (Gesbert et al. 1998) and IL-4 (Ueno et al. 1998).
Cbl is constitutively associated with Grb in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain binds the adaptor protein CRKL. Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). Cbl is tyrosine phosphorylated in response to many cytokines including IL-3, IL-2 (Gesbert et al. 1998) and IL-4 (Ueno et al. 1998).
所含基因
21 个基因