Endogenous and synthetic inhibitors of the Src-family protein tyrosine kinases
Endogenous and synthetic inhibitors of the Src-family protein tyrosine kinases
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DOI：
10.1016/j.bbapap.2005.07.027
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发表时间：
2005-12-30
影响因子：
3.2
通讯作者：
Cheng, HC
中科院分区：
文献类型：
--
作者：
Chong, YP;Ia, KK;Cheng, HC
Src家族激酶（SFKs）是控制哺乳动物细胞生长和增殖的原癌基因酶。SFK的活性主要由两个酪氨酸磷酸化位点调节：激酶结构域中保守酪氨酸（Y-A）的自磷酸化导致激活，而C-末端附近的调节酪氨酸（Y-T）的磷酸化导致失活。磷酸化的Y-T（pY（T））参与分子内相互作用，稳定SFK的非活性构象。这些抑制性分子内相互作用包括pY（T）与SH 2结构域的结合和SH 2-激酶接头与SH 3结构域的结合。因此，SFK在（i）抑制性分子内相互作用的破坏，（ii）YA的自磷酸化和/或（iii）pY（T）的去磷酸化时是有活性的。由于SFK的异常激活有助于癌症，正常细胞中的SFK被多种内源性抑制剂保持无活性，所述内源性抑制剂被分类为催化和非催化抑制剂。催化抑制剂包括使SFK的Y-T磷酸化的C-末端Src激酶（CSK）和CSK同源激酶（CHK），以及使活化的SFK的pY（A）去磷酸化的蛋白酪氨酸磷酸酶。非催化抑制剂通过直接结合来抑制SFKs。CHK在这些抑制剂中是独特的，因为它采用催化和非催化机制来抑制SFK。其他已知的非催化抑制剂包括WASP、小窝蛋白和RACK 1，其功能是下调特定亚细胞位置的SFK。本文综述了多种内源性SFK抑制剂如何协同调节正常细胞中的SFK。由于能选择性抑制SFKs的化合物是潜在的抗癌药物，本文还讨论了内源性抑制剂的抑制机制的研究将有利于这些化合物的设计和筛选。(c)2005 Elsevier B.V保留所有权利。
Src-family kinases (SFKs) are protooncogenic enzymes controlling mammalian cell growth and proliferation. The activity of SFKs is primarily regulated by two tyrosine phosphorylation sites: autophosphorylation of a conserved tyrosine (Y-A) in the kinase domain results in activation while phosphorylation of the regulatory tyrosine (Y-T) near the C-terminus leads to inactivation. The phosphorylated Y-T (pY(T)) engages in intramolecular interactions that stabilise the inactive conformation of SFKs. These inhibitory intramolecular interactions include the binding of pY(T) to the SH2 domain and the binding of the SH2-kinase linker to the SH3 domain. Thus, SFKs are active upon (i) disruption of the inhibitory intramolecular interactions, (ii) autophosphorylation of YA and/or (iii) dephosphorylation of pY(T). Since aberrant activation of SFKs contributes to cancer, SFKs in normal cells are kept inactive by multiple endogenous inhibitors classified as catalytic and non-catalytic inhibitors. The catalytic inhibitors include C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) that phosphorylate Y-T of SFKs, as well as the protein tyrosine phosphatases that dephosphorylate pY(A) of the activated SFKs. The non-catalytic inhibitors inactivate SFKs by direct binding. CHK is unique among these inhibitors because it employs both catalytic and non-catalytic mechanisms to inhibit SFKs. Other known non-catalytic inhibitors include WASP, caveolin and RACK1, which function to down-regulate SFKs in specific subcellular locations. This review discusses how the various endogenous SFK inhibitors cooperate to regulate SFKs in normal cells. As chemical compounds that can selectively inhibit SFKs in vivo are potential anticancer therapeutics, this review also discusses how investigation into the inhibitory mechanisms of the endogenous inhibitors will benefit the design and screening of these compounds. (c) 2005 Elsevier B.V All rights reserved.