Human insulin receptor juxtamembrane domain independent insulin signaling.
Human insulin receptor juxtamembrane domain independent insulin signaling.
复制标题
人胰岛素受体近膜结构域独立的胰岛素信号传导。
DOI：
10.1016/j.cellbi.2007.01.033
复制
发表时间：
2007
影响因子：
3.9
通讯作者：
Berhanu,Paulos
中科院分区：
文献类型：
--
作者：
Sattar,AkmA;Berhanu,Chali;Gebreselassie,Surafel;Berhanu,Paulos
人胰岛素受体 (hIR) 的外显子 16 编码的近膜 (JM) 结构域包含 NPEY 基序，该基序将胰岛素激活的 hIR 激酶与下游信号转导分子偶联。我们试图确定信号转导是否需要整个外显子 16 编码的 22 个氨基酸 JM 结构域。转染的 CHO 细胞稳定表达野生型 hIR (hIR-WT) 或两种突变型 hIR（其中 JM 结构域被删除的 hIRΔEx16，以及其中删除的片段被 v-ros 蛋白的相应结构域取代的 hIRrosJM）。突变体 hIRΔEx16 和 hIRrosJM 表现出与 hIRWT 相似的胰岛素结合作用。针对下游信号转导分子激活的胰岛素内化和胰岛素剂量反应实验表明：i）包含 NPEY 基序的完整 hIR-JM 结构域的存在对于 Shc 磷酸化至关重要，但对于 IRS-1 磷酸化则不然； ii) 胰岛素信号转导可以独立于 hIR 的 JM 结构域而发生，并且无需 NPEY 基序的参与； iii) 这种假定的替代下游信号转导的参与是独立于 Shc 的并且依赖于胰岛素浓度； iv) 胰岛素内化不一定需要 JM 结构域的 hIR 特异性 aa 序列，该序列可以被 v-ros 酪氨酸激酶的 JM 结构域部分取代。
The exon 16‐encoded juxtamembrane (JM) domain of human insulin receptor (hIR) harbors the NPEY motif which couples the insulin‐activated hIR kinase to downstream signal transduction molecules. We sought to determine if signal transduction requires the entire exon 16‐encoded 22‐amino acid JM domain. Transfected CHO cells were generated stably expressing either the wild‐type hIR (hIR‐WT) or two mutant hIRs (hIRΔEx16 in which the JM domain was deleted, and hIRrosJM in which the deleted segment was replaced by the corresponding domain of v‐ros protein). The mutant hIRΔEx16 and hIRrosJM exhibited similar insulin‐binding as the hIRWT. Insulin internalization and insulin dose‐response experiments toward activation of downstream signal transduction molecules demonstrated that: i) the presence of intact hIR‐JM domain which harbors the NPEY motif is essential for Shc phosphorylation but not for IRS‐1 phosphorylation; ii) insulin signal transduction can occur independent of the JM domain of hIR and without participation of the NPEY motif; iii) engagement of this putative alternative downstream signal transduction is Shc independent and is dependent on insulin concentration; and iv) insulin internalization does not necessarily require the hIR specific aa sequence of the JM domain which can be partially substituted by the JM domain of the v‐ros tyrosine kinase.