Hedgehog 通路 'off' 状态
中文名称
通路描述
Hedgehog 是一种分泌的形态发生素，通过调节 Ci/Gli 转录因子家族的活性在身体组织中发挥进化上保守的作用。在果蝇中，当缺乏 Hh 信号时，全长 Ci 部分被蛋白酶体降解，生成截短的抑制形式，该形式可转运至细胞核以抑制 Hh 响应基因。Hh 配体与 Patched (PTC) 受体结合后，允许 7 次跨膜蛋白 Smoothened (SMO) 被激活（以未知方式），破坏 Ci 的部分蛋白酶体降解，允许全长激活形式积累（综述：Ingham 等，2011；Briscoe 和 Therond，2013）。虽然许多核心 Hh 信号通路组件从果蝇到人类是保守的，但通路也显示出显著的分化。值得注意的是，人类基因组编码三个 Ci 同源物 GLI1、2 和 3，它们在调节 Hh 响应基因方面发挥略有不同的作用。GLI3 是脊椎动物中 Hh 信号的主要抑制因子，在缺乏 Hh 时转化为截短的 GLI3R 抑制形式。GLI2 是 Hh 存在时的强效转录激活因子，但在抑制功能中贡献最小。虽然少量 GLI2 蛋白在缺乏 Hh 时被加工为抑制形式，但大部分要么被蛋白酶体完全降解，要么通过蛋白质 - 蛋白质相互作用被锁定在细胞质中的全长形式中。GLI1 缺乏抑制结构域，似乎是一个必需的转录激活因子（综述：Briscoe 和 Therond，2013）。脊椎动物但非果蝇的 Hh 信号还依赖于通路组件通过初级纤毛的移动。初级纤毛是一种非运动性的微管结构，其构建和维持依赖于内纤毛运输 (IFT)。顺向 IFT 将分子从纤毛基部沿轴丝移动到纤毛尖端，这需要微管正端定向的 KIF3 肌球蛋白复合体和 IFT-B 蛋白复合体，而逆向 IFT 则依赖于微管负端定向的驱动蛋白和 IFT-A 复合体。基因筛选已鉴定出一系列纤毛相关蛋白，它们既需要维持 Hh 处于 'off' 状态，也需要在通路激活时传递信号（综述：Hui 和 Angers，2011；Goetz 和 Anderson，2010）。
英文描述
Downregulation of TGF-beta receptor signaling TGF-beta receptor signaling is downregulated by proteasome and lysosome-mediated degradation of ubiquitinated TGFBR1, SMAD2 and SMAD3, as well as by dephosphorylation of TGFBR1, SMAD2 and SMAD3.
In the nucleus, SMAD2/3:SMAD4 complex stimulates transcription of SMAD7, an inhibitory SMAD (I-SMAD). SMAD7 binds phosphorylated TGFBR1 and competes with the binding of SMAD2 and SMAD3 (Hayashi et al. 1997, Nakao et al. 1997). Binding of SMAD7 to TGBR1 can be stabilized by STRAP, a protein that simultaneously binds SMAD7 and TGFBR1 (Datta et al. 2000). BAMBI simultaneously binds SMAD7 and activated TGFBR1, leading to downregulation of TGF-beta receptor complex signaling (Onichtchouk et al. 1999, Yan et al. 2009).
In addition to competing with SMAD2/3 binding to TGFBR1, SMAD7 recruits protein phosphatase PP1 to phosphorylated TGFBR1, by binding to the PP1 regulatory subunit PPP1R15A (GADD34). PP1 dephosphorylates TGFBR1, preventing the activation of SMAD2/3 and propagation of TGF-beta signal (Shi et al. 2004).
SMAD7 associates with several ubiquitin ligases, SMURF1 (Ebisawa et al. 2001, Suzuki et al. 2002, Tajima et al. 2003, Chong et al. 2010), SMURF2 (Kavsak et al. 2000, Ogunjimi et al. 2005), and NEDD4L (Kuratomi et al. 2005), and recruits them to phosphorylated TGFBR1 within TGFBR complex. SMURF1, SMURF2 and NEDD4L ubiquitinate TGFBR1 (and SMAD7), targeting TGFBR complex for proteasome and lysosome-dependent degradation (Ebisawa et al. 2001, Kavsak et al. 2000, Kuratomi et al. 2005). The ubiquitination of TGFBR1 can be reversed by deubiquitinating enzymes, UCHL5 (UCH37) and USP15, which may be recruited to ubiquitinated TGFBR1 by SMAD7 (Wicks et al. 2005, Eichhorn et al. 2012).
Basal levels of SMAD2 and SMAD3 are maintained by SMURF2 and STUB1 ubiquitin ligases. SMURF2 is able to bind and ubiquitinate SMAD2, leading to SMAD2 degradation (Zhang et al. 2001), but this has been questioned by a recent study of Smurf2 knockout mice (Tang et al. 2011). STUB1 (CHIP) binds and ubiquitinates SMAD3, leading to SMAD3 degradation (Li et al. 2004, Xin et al. 2005). PMEPA1 can bind and sequester unphosphorylated SMAD2 and SMAD3, preventing their activation in response to TGF-beta signaling. In addition, PMEPA1 can bind and sequester phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimer complexes (Watanabe et al. 2010). A protein phosphatase MTMR4, residing in the membrane of early endosomes, can dephosphorylate activated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 complexes (Yu et al. 2010).
In the nucleus, SMAD2/3:SMAD4 complex stimulates transcription of SMAD7, an inhibitory SMAD (I-SMAD). SMAD7 binds phosphorylated TGFBR1 and competes with the binding of SMAD2 and SMAD3 (Hayashi et al. 1997, Nakao et al. 1997). Binding of SMAD7 to TGBR1 can be stabilized by STRAP, a protein that simultaneously binds SMAD7 and TGFBR1 (Datta et al. 2000). BAMBI simultaneously binds SMAD7 and activated TGFBR1, leading to downregulation of TGF-beta receptor complex signaling (Onichtchouk et al. 1999, Yan et al. 2009).
In addition to competing with SMAD2/3 binding to TGFBR1, SMAD7 recruits protein phosphatase PP1 to phosphorylated TGFBR1, by binding to the PP1 regulatory subunit PPP1R15A (GADD34). PP1 dephosphorylates TGFBR1, preventing the activation of SMAD2/3 and propagation of TGF-beta signal (Shi et al. 2004).
SMAD7 associates with several ubiquitin ligases, SMURF1 (Ebisawa et al. 2001, Suzuki et al. 2002, Tajima et al. 2003, Chong et al. 2010), SMURF2 (Kavsak et al. 2000, Ogunjimi et al. 2005), and NEDD4L (Kuratomi et al. 2005), and recruits them to phosphorylated TGFBR1 within TGFBR complex. SMURF1, SMURF2 and NEDD4L ubiquitinate TGFBR1 (and SMAD7), targeting TGFBR complex for proteasome and lysosome-dependent degradation (Ebisawa et al. 2001, Kavsak et al. 2000, Kuratomi et al. 2005). The ubiquitination of TGFBR1 can be reversed by deubiquitinating enzymes, UCHL5 (UCH37) and USP15, which may be recruited to ubiquitinated TGFBR1 by SMAD7 (Wicks et al. 2005, Eichhorn et al. 2012).
Basal levels of SMAD2 and SMAD3 are maintained by SMURF2 and STUB1 ubiquitin ligases. SMURF2 is able to bind and ubiquitinate SMAD2, leading to SMAD2 degradation (Zhang et al. 2001), but this has been questioned by a recent study of Smurf2 knockout mice (Tang et al. 2011). STUB1 (CHIP) binds and ubiquitinates SMAD3, leading to SMAD3 degradation (Li et al. 2004, Xin et al. 2005). PMEPA1 can bind and sequester unphosphorylated SMAD2 and SMAD3, preventing their activation in response to TGF-beta signaling. In addition, PMEPA1 can bind and sequester phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimer complexes (Watanabe et al. 2010). A protein phosphatase MTMR4, residing in the membrane of early endosomes, can dephosphorylate activated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 complexes (Yu et al. 2010).
所含基因
25 个基因