假激酶在细胞信号转导中的功能

The Functions of Pseudokinases in Cellular Signal Transduction

蛋白质激酶是一个庞大的蛋白质家族,参与了真核细胞的绝大部分信号转导。激酶的磷酸化功能已得到较为深入的研究,而一些激酶在进化过程中由于关键模体的关键氨基酸突变/缺失而失去了激酶活性,称之为“假激酶”。假激酶在不同物种间是保守的,这一现象说明它们虽然不具备磷酸化活性,但可能具有其他一些非磷酸化功能。最近的研究证实,假激酶具有这些非磷酸化功能,并以此参与细胞内信号转导,包括:(1)通过直接结合活性激酶调控其磷酸化活性;(2)通过竞争抑制调控活性激酶的磷酸化活性;(3)作为分子开关发挥不依赖激酶的关键非催化功能;(4)作为信号支架辅助信号转导;(5)发挥磷酸化活性之外的催化功能。这些功能已被证明参与发育、免疫和代谢等重要的生理过程。假激酶的突变或表达异常与多种疾病例如肿瘤、神经系统疾病、代谢性疾病和自身免疫性疾病的发生相关。本文就假激酶在细胞信号转导中的功能进行了概述,并对其未来研究方向进行了展望。

Protein kinases regulate signaling pathways in eukaryotic cells.The phosphorylation function of kinases has attracted the attention of scientists and been deeply studied.However,some kinases are called“pseudokinases”due to missing of the key amino acids in the key motif during evolution,which leads to disruption of their phosphoryl-transfer activity.The fact that these pseudokinases are conserved across species argues that although pseudokinases have lost their phosphoryl-transfer activity,they may acquire the phosphorylation-independent functions and participate in the cellular signal transduction as well.The phosphorylation-independent functions of pseudokinases are listed as follows:1.Directly regulating the phosphorylation activity of active kinases by binding with them;2.Regulating the phosphorylation activity of active kinases by competitive inhibition;3.Acting as molecular switches to perform key non-catalytic functions;4.Acting as signaling scaffolds to assist in cell signaling;5.Exerting catalytic functions other than phosphorylation activity.These functions have been shown to be involved in important physiological processes such as development,immunity and metabolism.Mutations or abnormal expression of pseudokinases are associated with the occurrence of various diseases such as tumors,neurological diseases,metabolic diseases and autoimmune diseases.In this article,we summarize the functions of pseudokinases in cellular signal transduction and provide a perspective for the future directions in the study of pseudokinases.