A network of serine kinases is involved in the downregulation of insulin signaling

Среди них мутации генов, кодирующих белки, субстраты инсулинового рецептора (IRS-1 и IRS-2), фосфатидилинозитол-3-киназу, а также нижележащие звенья, в том числе фактор некроза опухолей a.

Наряду с мутациями гена, кодирующего рецептор инсулина, а также нарушением синтеза, процессинга и циркуляции рецепторов, нарушение функциональной активности других компонентов инсулиновой сигнальной системы также приводит к развитию инсулиновой резистентности.

Serine phosphorylation sites in IRS proteins and serine kinases involved. Serine phosphorylation of IRS proteins is a mechanism shared by insulin and several inducers of insulin resistance such as inflammatory cytokines, free fatty acids, ROS. In physiological conditions insulin induces the phosphorylation of an array of sites in time-controlled manner. Positive regulatory sites (+) are phosphorylated first by kinases in the insulin signaling pathways such as PKB and PKCζ. This phosphorylation allows a correct tyrosine phosphorylation of IRS1 and the propagation of the insulin signal. Inhibitory sites (−) are phosphorylated later on by PKCζ and mTOR/S6K and decrease the tyrosine phosphorylation of IRS1 leading to the termination of the insulin signal. Some sites have both positive and negative (+/−) effects depending on the time course of phosphorylation and the phosphorylation of other sites. In pathophysiological conditions, inducers of insulin resistance activate several serine kinases such as IKKβ, JNK, ERK, S6K that phosphorylate IRS1 protein on inhibitory sites in an uncontrolled manner. Serine phosphorylation of IRS2 is also involved in the regulation of its tyrosine phosphorylation. The identification of serine and threonine phosphorylation sites and kinases is beginning. Phosphorylation of Ser488 by JNK primes Ser484 for phosphorylation by GSK-3 resulting in an inhibition of insulin signaling. JNK also phosphorylates the Threonine348 located at the end of the PTB domain. By analogy with IRS1, this phosphorylation may disrupt the interaction between IR and IRS2. Abbreviation: PH, Pleckstrin homology domain; PTB, phosphotyrosine binding domain; KRLB, kinase regulatory-loop binding domain; BD, binding sites; h, numbering according to human IRS1 sequence.

In obesity and diabetes, a network of serine kinases is activated that targets IRS proteins and downregulates insulin signaling. Some of these kinases such as PKCζ and mTORC1/S6K are in the insulin signaling pathway (in grey in the figure). They are involved in both the propagation of the insulin signal and its termination through a negative feedback mechanism. Other kinases (in pink in the figure) are more specifically activated by inflammatory cytokines, fatty acids, amino acids, and ROS. IRS proteins are major targets of the network of kinases and some of them are involved in the inflammatory state linked to obesity (see text for details). Abbreviation: IR, insulin receptor; IRS, insulin receptor substrate; PI3K phosphatidylinositol 3-kinase; mTORC, mammalian target of rapamycin complex; ERK, extracellular signal regulated kinase; JNK, c-Jun N-terminal kinase; SOCS, suppressor of cytokines signaling; ER stress, endoplasmic reticulum stress; IKKβ, inhibitory-κB kinase β; NF-κB, nuclear factor-κB; PTP1B, protein tyrosine phosphatase 1B.

Дата добавления: 2014-01-14