Src family kinases: Regulation of their activities, levels and identification of new pathways
Src family kinases: Regulation of their activities, levels and identification of new pathways
复制标题
DOI：
10.1016/j.bbapap.2007.08.012
复制
发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Ingley, Evan
中科院分区：
文献类型：
--
作者：
Ingley, Evan
虽然Src家族的蛋白酪氨酸激酶（SFK），和参与其调节的主要辅助分子，已经研究了多年，它们的相互作用的细节还没有完全理解，因此仍然在积极的调查。此外，还发现了协调其监管和指导其信号级联的新参与者，从而为这些信号网络的复杂性提供了新的线索。通过利用新的相互作用试验，已经发现了几个新的相互连接的介质，有助于显示Src家族激酶调节的优雅。本文综述了SFK的调节，Csk结合蛋白（与鞘糖脂富集的微结构域相关的磷蛋白，Cbp/PAG）的发现，及其在调节SFK激酶活性状态，以及蛋白水平中的作用。此外，用于鉴定这种双重调节模式的方法的细节可以应用于描绘SH 2/SH 3介导的SFK途径的全部范围，实际上，任何酪氨酸激酶的全部范围。使用林恩作为SFK模型，我们和其他人已经表明，在林恩被激活并与Cbp结合后，Cbp招募COOH末端Src激酶（Csk）/Csk样蛋白酪氨酸激酶（Ctk）的负调节因子。林恩磷酸化多个酪氨酸残基上的Cbp，包括可以以高亲和力结合林恩的SH 2结构域的两个。林恩也磷酸化Y314，其募集Csk/Ctk在其Y508负位点磷酸化林恩，允许形成无活性构象。然而，pY 508位点对林恩的SH 2结构域具有低亲和力，而Cbp位点具有高亲和力。因此，直到这些Cbp位点被去磷酸化，林恩可以保持活性。有趣的是，磷酸化的Y314还结合细胞因子信号传导抑制因子I（SOCS 1），导致林恩的泛素化和降解升高。因此，一个单一的磷酸酪氨酸残基内Cbp协调一个两阶段的过程，涉及不同的负调控途径，允许失活，然后降解，SFKs。(C)2007 Elsevier B. V.保留所有权利。
While the Src family of protein tyrosine kinases (SFK), and the main ancillary molecules involved in their regulation, have been studied for many years, the details of their interplay are not fully understood and thus remain under active investigation. Additionally, new players that coordinate their regulation and direct their signalling cascades are also being uncovered, shedding new light on the complexity of these signalling networks. Through the utilization of novel interaction assays, several new interconnecting mediators that are helping to show the elegance of Src family kinase regulation have been discovered. This review outlines SFK regulation, the discovery of the Csk binding protein (Phosphoprotein Associated with Glycosphingolipid-enriched microdomains, Cbp/PAG), and its role in regulating SFK kinase activity status, as well as protein levels. Further, details of the methods used to identify this dual mode of regulation can be applied to delineate the full gamut of SH2/SH3-directed SFK pathways and, indeed, those of any tyrosine kinase. Using Lyn as a model SFK, we and others have shown that Cbp recruits negative regulators of COOH-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk) after Lyn is activated and bound to Cbp. Lyn phosphorylates Cbp on multiple tyrosine residues, including two that can bind Lyn's SH2 domain with high affinity. Lyn also phosphorylates Y314, which recruits Csk/Ctk to phosphorylate Lyn at its Y508 negative site, allowing an inactive conformation to form. However, the pY508 site has a low affinity for Lyn's SH2 domain, while the Cbp sites have high affinity. Thus, until these Cbp sites are dephosphorylated, Lyn can remain active. Intriguingly, phosphorylated Y314 also binds the suppressor of cytokine signalling I (SOCS1), resulting in elevated ubiquitination and degradation of Lyn. Thus, a single phosphotyrosine residue within Cbp co-ordinates a two-phase process involving distinct negative regulatory pathways that allow inactivation, followed by degradation, of SFKs. (C) 2007 Elsevier B.V. All rights reserved.