Insulin receptor-associated protein tyrosine phosphatase(s): Role in insulin action
Insulin receptor-associated protein tyrosine phosphatase(s): Role in insulin action
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DOI：
10.1023/a:1006808100755
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发表时间：
1998-05-01
影响因子：
4.3
通讯作者：
Posner, BI
中科院分区：
文献类型：
--
作者：
Drake, PG;Posner, BI
蛋白酪氨酸磷酸酶(PTPs)在调节胰岛素的作用中起着关键作用，部分是通过使胰岛素受体(IRK)的活性(自动磷酸化)去磷酸化和降低其酪氨酸激酶活性来实现的。胰岛素结合后，激活的IRK被迅速内化到内体器官中，这是体内IRK去磷酸化的主要部位。对大鼠肝脏的研究表明，PTPs可能通过选择性的irk酪氨酸去磷酸化作用，以积极和消极的方式调节irk活性，这是一个复杂的调控过程。过氧钒(PV)化合物被证明是一种有效的PTP抑制剂，在描述体内IRK及其相关PTP(S)之间的密切关系方面，使用过氧钒化合物至关重要。事实上，体内给药的PV化合物在激活IRK的同时抑制了IRK相关的PTP活性。这一过程伴随着正常大鼠和糖尿病大鼠血糖水平的降低，从而表明IRK相关的PTP(S)是定义一类新的胰岛素模拟剂的合适靶点。发现生理上相关的IRK相关PTP(S)应有助于开发适用于治疗糖尿病的药物。
Protein tyrosine phosphatases (PTPs) play a critical role in regulating insulin action in part through dephosphorylation of the active (autophosphorylated) form of the insulin receptor (IRK) and attenuation of its tyrosine kinase activity. Following insulin binding the activated IRK is rapidly internalized into the endosomal apparatus, a major site at which the IRK is dephosphorylated in vivo. Studies in rat liver suggest a complex regulatory process whereby PTPs may act, via selective IRK tyrosine dephosphorylation, to modulate IRK activity in both a positive and negative manner. Use of peroxovanadium (pV) compounds, shown to be powerful PTP inhibitors, has been critical in delineating a close relationship between the IRK and its associated PTP(s) in vivo. Indeed the in vivo administration of pV compounds effected activation of IRK in parallel with an inhibition of IRK-associated PTP activity. This process was accompanied by a lowering of blood glucose levels in both normal and diabetic rats thus implicating the IRK-associated PTP(s) as a suitable target for defining a novel class of insulin mimetic agents. Identification of the physiologically relevant IRK-associated PTP(s) should facilitate the development of drugs suitable for managing diabetes mellitus.