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首页> 外文期刊>The FEBS journal >Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines
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Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines

机译：瘦素受体信号的多向性由细胞内酪氨酸的不同作用来定义

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The leptin receptor (LEPR) is a class I cytokine receptor signalling via both the janus kinase/signal transducer and activator of transcription (JAK/STAT) and the MAP kinase pathways. In addition, leptin has been shown previously to activate AMP-activated kinase (AMPK) in skeletal muscle. To enable a detailed analysis of leptin signalling in pancreatic beta cells, LEPR point mutants with single or combined exchanges of the three intracellular tyrosines were expressed in HIT-T15 insulinoma cells. Western blots with activation state-specific antibodies recognizing specific signalling molecules revealed that the wild-type receptor activated STAT1, STAT3, STAT5 and ERK1/2 but failed to alter the phosphorylation of AMPK. Each of the three intracellular tyrosine residues in LEPR exhibited different signalling capacities: Tyr985 was necessary and sufficient for leptin-induced activation of ERK1/2; Tyr1077 induced tyrosyl phosphorylation of STAT5; and Tyr1138 was capable of activating STAT1, STAT3 and STAT5. Consistent results were obtained in reporter gene assays with STAT3 or STAT5-responsive promoter constructs, respectively. Furthermore, the sequence motifs surrounding the three tyrosine residues are conserved in LEPR from mammals, birds and in a LEPR-like cytokine receptor from pufferfish. Mutational analysis of the box3 motif around Tyr1138 identified Met1139 and Gln1141 as important determinants that define specificity towards the different STAT factors. These data indicate that all three conserved tyrosines are involved in LEPR function and define the pleiotropy of signal transduction via STAT1/3, STAT5 or ERK kinases. Activation and inhibition of AMPK appears to require additional components of the signalling pathways that are not present in beta cells.
机译：瘦素受体（LEPR）是通过janus激酶/信号转导子和转录激活子（JAK / STAT）和MAP激酶途径进行的I类细胞因子受体信号转导。另外，瘦素以前已经显示出可以激活骨骼肌中的AMP激活的激酶（AMPK）。为了能够详细分析胰岛β细胞中的瘦素信号传导，在HIT-T15胰岛素瘤细胞中表达了具有三个细胞内酪氨酸的单个或组合交换的LEPR点突变体。带有识别特定信号分子的激活状态特异性抗体的蛋白质印迹表明，野生型受体激活了STAT1，STAT3，STAT5和ERK1 / 2，但未能改变AMPK的磷酸化。 LEPR的三个细胞内酪氨酸残基均表现出不同的信号传导能力：Tyr985对瘦蛋白诱导的ERK1 / 2激活是必需的，并且是足够的。 Tyr1077诱导STAT5酪氨酸磷酸化; Tyr1138能够激活STAT1，STAT3和STAT5。在分别使用STAT3或STAT5应答的启动子构建体的报告基因分析中获得了一致的结果。此外，围绕三个酪氨酸残基的序列基序在哺乳动物，鸟类的LEPR中以及在河豚的LEPR样细胞因子受体中是保守的。对Tyr1138周围box3基序的突变分析确定Met1139和Gln1141是重要的决定因素，这些决定因素确定了对不同STAT因子的特异性。这些数据表明，所有三个保守的酪氨酸都参与了LEPR功能，并定义了通过STAT1 / 3，STAT5或ERK激酶进行信号转导的多效性。 AMPK的激活和抑制似乎需要β细胞中不存在的信号传导途径的其他成分。

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