Human biliverdin reductase: A member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity
Human biliverdin reductase: A member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity
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DOI：
10.1073/pnas.0502173102
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发表时间：
2005-05-17
影响因子：
11.1
通讯作者：
Maines, MD
中科院分区：
文献类型：
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作者：
Lerner-Marmarosh, N;Shen, J;Maines, MD
我们在这里描述的酪氨酸激酶活性的人胆绿素还原酶（BVR）和它的潜在作用，在胰岛素信号通路。BVR既是胰岛素受体（IR）酪氨酸激酶（IRK）活性的底物，也是IR底物1（IRS-1）丝氨酸磷酸化的激酶。我们以前的研究已经揭示了BVR的丝氨酸/苏氨酸激酶活性。在BVR的C-末端结构域中发现的YMKM基序中的Y-198显示为胰岛素活化的IRK的底物。IRS蛋白中的这个基序为含有Src同源2结构域的蛋白提供了对接位点。此外，YLSF序列中的Y-228和Y-291是IRK底物;前者序列在酪氨酸磷酸酶SHP-1和SHC（含转化蛋白1的Src同源2结构域）中提供最佳识别基序。BVR自磷酸化N-末端酪氨酸Y-72和Y-83。IRS-1中的丝氨酸残基是BVR磷酸化的靶标，还原酶激酶结构域中丝氨酸残基的点突变抑制磷酸转移酶活性。由于IRS-1的酪氨酸磷酸化激活胰岛素信号通路，IRS-1的丝氨酸磷酸化阻断胰岛素作用，我们的研究结果表明，胰岛素增加BVR酪氨酸磷酸化，当BVR的表达被小干扰RNA“敲低”时，对胰岛素的葡萄糖摄取增加，这表明BVR在胰岛素信号通路中的潜在作用。
We describe here the tyrosine kinase activity of human biliverdin reductase (BVR) and its potential role in the insulin-signaling pathway. BVR is both a substrate for insulin receptor (IR) tyrosine kinase (IRK) activity and a kinase for serine phosphorylation of IR substrate 1 (IRS-1). Our previous studies have revealed serine/threonine kinase activity of BVR. Y-198, in the YMKM motif found in the C-terminal domain of BVR, is shown to be a substrate for insulin-activated IRK. This motif in IRS proteins provides a docking site for proteins that contain a Src homology 2 domain. Additionally, Y-228 in the YLSF sequence and Y-291 are IRK substrates; the former sequence provides optimum recognition motif in the tyrosine phosphatase, SHP-1, and for SHC (Src homology 2 domain containing transfroming protein 1). BVR autophosphorylates N-terminal tyrosines Y-72 and Y-83. Serine residues in IRS-1 are targets for BVR phosphorylation, and point mutation of serine residues in the kinase domain of the reductase inhibits phosphotransferase activity. Because tyrosine phosphorylation of IRS-1 activates the insulin signaling pathway and serine phosphorylation of IRS-1 blocks insulin action, our findings that insulin increases BVR tyrosine phosphorylation and that there is an increase in glucose uptake in response to insulin when expression of BVR is "knocked down" by small interfering RNA suggest a potential role for BVR in the insulin signaling pathway.