A Drosophila model of insulin resistance associated with the human TRIB3 Q/R polymorphism.
A Drosophila model of insulin resistance associated with the human TRIB3 Q/R polymorphism.
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DOI：
10.1242/dmm.030619
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发表时间：
2017-12-19
影响因子：
4.3
通讯作者：
Dobens LL
中科院分区：
文献类型：
--
作者：
Fischer Z;Das R;Shipman A;Fan JY;Pence L;Bouyain S;Dobens LL
Tribbles蛋白家族的成员是保守的假激酶，在细胞生长和增殖中具有不同的作用。果蝇Tribbles（Trbl）和脊椎动物Trib3蛋白都与激酶Akt（Akt1）结合，以阻断其磷酸化激活并减少下游胰岛素刺激的抗凋亡。人TRIB 3中的单核苷酸多态性（SNP）变体导致第84位保守基序中的谷氨酰胺（Q）至精氨酸（R）错义突变，赋予更强的Akt结合，导致Akt磷酸化降低，并且与2型糖尿病、心血管疾病、糖尿病肾病、慢性肾病和白血病发生的易感性相关。在这里，我们使用果蝇模型来了解保守的R残基在几个Trbl功能的重要性。在果蝇脂肪体中，R141位点定向Q突变的错误表达导致与果蝇Akt（dAkt）的结合减弱，导致磷酸化dAkt水平增加，细胞和组织大小增加，储存糖原和甘油三酯水平增加。与该精氨酸在调节Akt活性中的功能保守性一致，在蝇脂肪体中错误表达的小鼠Trib3 R84以与野生型Trbl类似的强度阻断dAkt磷酸化。有限的突变分析表明，R141位点决定Akt结合的强度，但不影响其他Trbl依赖性发育过程，这表明可以作为代谢疾病的药物靶点的特异性。总结：与II型糖尿病相关的胰岛素信号传导抑制剂tribbles 3（TRIB3）变体在果蝇模型系统中对Tribbles调节的胰岛素信号传导、生长和Akt活化具有平行作用。
Members of the Tribbles family of proteins are conserved pseudokinases with diverse roles in cell growth and proliferation. Both Drosophila Tribbles (Trbl) and vertebrate Trib3 proteins bind to the kinase Akt (Akt1) to block its phosphorylation activation and reduce downstream insulin-stimulated anabolism. A single nucleotide polymorphism (SNP) variant in human TRIB3, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding, resulting in reduced Akt phosphorylation, and is associated with a predisposition to Type 2 diabetes, cardiovascular disease, diabetic nephropathy, chronic kidney disease and leukemogenesis. Here, we used a Drosophila model to understand the importance of the conserved R residue in several Trbl functions. In the fly fat body, misexpression of a site-directed Q mutation at position R141 resulted in weakened binding to Drosophila Akt (dAkt), leading to increased levels of phospho-dAkt, increased cell and tissue size, and increases in the levels of stored glycogen and triglycerides. Consistent with the functional conservation of this arginine in modulating Akt activity, mouse Trib3 R84 misexpressed in the fly fat body blocked dAkt phosphorylation with a strength similar to wild-type Trbl. Limited mutational analysis shows that the R141 site dictates the strength of Akt binding but does not affect other Trbl-dependent developmental processes, suggesting a specificity that could serve as a drug target for metabolic diseases. Summary: The insulin signaling inhibitor tribbles 3 (TRIB3) variant associated with Type II diabetes has parallel effects in a fly model system on Tribbles-regulated insulin signaling, growth and Akt activation.
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影响因子：
11.8
作者：
Figueroa-Clarevega, Alejandra;Bilder, David
通讯作者：
Bilder, David
影响因子：
--
作者：
BUTTERWORTH, FM;BODENSTEIN, D;KING, RC
通讯作者：
KING, RC
DOI：
10.1534/g3.113.006676
发表时间：
2013-08-07
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Dobens AC;Dobens LL
通讯作者：
Dobens LL
2型糖尿病易感性变异对定量血糖特征的影响揭示了机械异质性。
影响因子：
7.7
作者：
Dimas AS;Lagou V;Barker A;Knowles JW;Mägi R;Hivert MF;Benazzo A;Rybin D;Jackson AU;Stringham HM;Song C;Fischer-Rosinsky A;Boesgaard TW;Grarup N;Abbasi FA;Assimes TL;Hao K;Yang X;Lecoeur C;Barroso I;Bonnycastle LL;Böttcher Y;Bumpstead S;Chines PS;Erdos MR;Graessler J;Kovacs P;Morken MA;Narisu N;Payne F;Stancakova A;Swift AJ;Tönjes A;Bornstein SR;Cauchi S;Froguel P;Meyre D;Schwarz PE;Häring HU;Smith U;Boehnke M;Bergman RN;Collins FS;Mohlke KL;Tuomilehto J;Quertemous T;Lind L;Hansen T;Pedersen O;Walker M;Pfeiffer AF;Spranger J;Stumvoll M;Meigs JB;Wareham NJ;Kuusisto J;Laakso M;Langenberg C;Dupuis J;Watanabe RM;Florez JC;Ingelsson E;McCarthy MI;Prokopenko I;MAGIC Investigators
通讯作者：
MAGIC Investigators
DOI：
10.1161/atvbaha.108.162883
发表时间：
2008-07-01
影响因子：
8.7
作者：
Andreozzi, Francesco;Formoso, Gloria;Sesti, Giorgio
通讯作者：
Sesti, Giorgio