瘦素信号传导
中文名称
通路描述
瘦素（LEP, OB, OBS）是一种循环脂肪因子，其受体为 LEPR（DB, OBR），控制食物摄入和能量平衡，与肥胖相关疾病有关（最近综述在 Amitani 等人 2013 年、Dunmore 和 Brown 2013 年、Cottrell 和 Mercer 2012 年、La Cava 2012 年、Marroqui 等人 2012 年、Paz-Filho 等人 2012 年、Denver 等人 2011 年、Lee 2011 年、Marino 等人 2011 年、Morton 和 Schwartz 2011 年、Scherer 和 Buettner 2011 年、Shan 和 Yeo 2011 年、Wauman 和 Tavernier 2011 年、Dardeno 等人 2010 年、Bjorbaek 2009 年、Myers 等人 2008 年、Myers 等人 2008 年），包括癌症（Guo 等人 2012 年）、炎症（Newman 和 Gonzalez-Perez 2013 年、Iikuni 等人 2008 年）和血管生成（Gonzalez-Perez 等人 2013 年）。在老鼠中发现瘦素基因（ob 或 LEP）和瘦素受体基因（Ob-R, db 或 LEPR）基因的自发突变打开了肥胖研究的新领域。瘦素被确定为由受 ob（肥胖）突变影响的基因产生的产物，该突变在老鼠中引起肥胖。同样，LEPR 是由受 db（糖尿病）突变影响的基因产生的。瘦素与 LEPR 结合诱导多种细胞类型中的经典（JAK2/STATs; MAPK/ERK 1/2, PI-3K/AKT）和非经典信号通路（PKC, JNK, p38 MAPK 和 AMPK）。瘦素与长形式 LEPR（OB-Rl）的结合启动磷酸化级联，导致 STAT5 和 STAT3 转录因子的转录激活以及 PI3K 通路的激活（未在此显示），MAPK/ERK 通路和 mTOR/S6K 通路。较短的 LEPR 异构体具有截短的细胞内结构域，无法激活 STAT 通路，但可以通过激活 JAK2、IRS-1 或 ERK 等传递信号，包括 MAPKs，然而它们在能量稳态中的作用尚未完全确定。已鉴定出几种 LEPR 异构体（综述在 Gorska 等人 2010 年）。长形式（LEPRb, OBRb）在 hypothalamus 和所有类型的免疫细胞中表达。它是唯一已知在响应瘦素时能完全激活信号通路的异构体。较短的异构体（LEPRa, LEPRc, LEPRd 和一种可溶性异构体 LEPRe）能够与 JAK 激酶相互作用并激活其他通路，然而它们在能量稳态中的作用尚未完全确定。
英文描述
Signaling by Leptin Leptin (LEP, OB, OBS), a circulating adipokine, and its receptor LEPR (DB, OBR) control food intake and energy balance and are implicated in obesity-related diseases (recently reviewed in Amitani et al. 2013, Dunmore and Brown 2013, Cottrell and Mercer 2012, La Cava 2012, Marroqui et al. 2012, Paz-Filho et al. 2012, Denver et al. 2011, Lee 2011, Marino et al. 2011, Morton and Schwartz 2011, Scherer and Buettner 2011, Shan and Yeo 2011, Wauman and Tavernier 2011, Dardeno et al. 2010, Bjorbaek 2009, Morris and Rui 2009, Myers et al. 2008), including cancer (Guo et al. 2012), inflammation (Newman and Gonzalez-Perez 2013, Iikuni et al. 2008), and angiogenesis (Gonzalez-Perez et al. 2013).
The identification of spontaneous mutations in the leptin gene (ob or LEP) and the leptin receptor gene (Ob-R, db or LEPR) genes in mice opened up a new field in obesity research. Leptin was discovered as the product of the gene affected by the ob (obesity) mutation, which causes obesity in mice. Likewise LEPR is the product of the gene affected by the db (diabetic) mutation. Leptin binding to LEPR induces canonical (JAK2/STATs; MAPK/ERK 1/2, PI-3K/AKT) and non-canonical signaling pathways (PKC, JNK, p38 MAPK and AMPK) in diverse cell types. The binding of leptin to the long isoform of LEPR (OB-Rl) initiates a phosphorylation cascade that results in transcriptional activation of target genes by STAT5 and STAT3 and activation of the PI3K pathway(not shown here), the MAPK/ERK pathway, and the mTOR/S6K pathway. Shorter LEPR isoforms with truncated intracellular domains are unable to activate the STAT pathway, but can transduce signals by way of activation of JAK2, IRS-1 or ERKs, including MAPKs.
LEPR is constitutively bound to the JAK2 kinase. Binding of LEP to LEPR causes a conformational change in LEPR that activates JAK2 autophosphorylation followed by phosphorylation of LEPR by JAK2. Phosphorylated LEPR binds STAT3, STAT5, and SHP2 which are then phosphorylated by JAK2. Phosphorylated JAK2 binds SH2B1 which then binds IRS1/2, resulting in phosphorylation of IRS1/2 by JAK2. Phosphorylated STAT3 and STAT5 dimerize and translocate to the nucleus where they activate transcription of target genes (Jovanovic et al. 2010). SHP2 activates the MAPK pathway. IRS1/2 activate the PI3K/AKT pathway which may be the activator of mTOR/S6K.
Several isoforms of LEPR have been identified (reviewed in Gorska et al. 2010). The long isoform (LEPRb, OBRb) is expressed in the hypothalamus and all types of immune cells. It is the only isoform known to fully activate signaling pathways in response to leptin. Shorter isoforms (LEPRa, LEPRc, LEPRd, and a soluble isoform LEPRe) are able to interact with JAK kinases and activate other pathways, however their roles in energy homeostasis are not fully characterized.
The identification of spontaneous mutations in the leptin gene (ob or LEP) and the leptin receptor gene (Ob-R, db or LEPR) genes in mice opened up a new field in obesity research. Leptin was discovered as the product of the gene affected by the ob (obesity) mutation, which causes obesity in mice. Likewise LEPR is the product of the gene affected by the db (diabetic) mutation. Leptin binding to LEPR induces canonical (JAK2/STATs; MAPK/ERK 1/2, PI-3K/AKT) and non-canonical signaling pathways (PKC, JNK, p38 MAPK and AMPK) in diverse cell types. The binding of leptin to the long isoform of LEPR (OB-Rl) initiates a phosphorylation cascade that results in transcriptional activation of target genes by STAT5 and STAT3 and activation of the PI3K pathway(not shown here), the MAPK/ERK pathway, and the mTOR/S6K pathway. Shorter LEPR isoforms with truncated intracellular domains are unable to activate the STAT pathway, but can transduce signals by way of activation of JAK2, IRS-1 or ERKs, including MAPKs.
LEPR is constitutively bound to the JAK2 kinase. Binding of LEP to LEPR causes a conformational change in LEPR that activates JAK2 autophosphorylation followed by phosphorylation of LEPR by JAK2. Phosphorylated LEPR binds STAT3, STAT5, and SHP2 which are then phosphorylated by JAK2. Phosphorylated JAK2 binds SH2B1 which then binds IRS1/2, resulting in phosphorylation of IRS1/2 by JAK2. Phosphorylated STAT3 and STAT5 dimerize and translocate to the nucleus where they activate transcription of target genes (Jovanovic et al. 2010). SHP2 activates the MAPK pathway. IRS1/2 activate the PI3K/AKT pathway which may be the activator of mTOR/S6K.
Several isoforms of LEPR have been identified (reviewed in Gorska et al. 2010). The long isoform (LEPRb, OBRb) is expressed in the hypothalamus and all types of immune cells. It is the only isoform known to fully activate signaling pathways in response to leptin. Shorter isoforms (LEPRa, LEPRc, LEPRd, and a soluble isoform LEPRe) are able to interact with JAK kinases and activate other pathways, however their roles in energy homeostasis are not fully characterized.
所含基因
10 个基因