Deciphering the cross talk between hnRNP K and c-Src: the c-Src activation domain in hnRNP K is distinct from a second interaction site
Deciphering the cross talk between hnRNP K and c-Src: the c-Src activation domain in hnRNP K is distinct from a second interaction site
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DOI：
10.1128/mcb.02014-06
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发表时间：
2007-03-01
影响因子：
5.3
通讯作者：
Ostareck-Lederer, Antje
中科院分区：
文献类型：
--
作者：
Adolph, Doerte;Flach, Nadine;Ostareck-Lederer, Antje
蛋白酪氨酸激酶c-Src受两种分子内相互作用的调节。抑制状态是通过Src同源2 （SH2）结构域与磷酸化的c末端尾部相互作用，以及SH3结构域与SH2与激酶结构域之间的连接区域形成的聚脯氨酸II型螺旋结合而实现的。hnRNP K是KH结构域蛋白家族的创始成员，参与染色质重塑、转录调控和特定mrna的翻译，是不同信号转导途径的靶点。特别是，它作为酪氨酸激酶c-Src的特异性激活剂和底物起作用。在这里，我们解决hnRNP K如何与c-Src相互作用和激活的问题。我们将hnRNP K中的脯氨酸残基定义为富含脯氨酸的基序P2（氨基酸[aa] 285至297）和P3（氨基酸[aa] 303至318），它们是c-Src特异性激活所必需的，我们剖析了hnRNP K中介导与c-Src第二次相互作用的氨基酸序列（aa 216至226）。我们的研究结果表明，与c-Src的相互作用和激酶的激活是hnRNP K的可分离功能。hnRNP K作为一种支架蛋白，通过促进介导核酸导向过程的激酶和因子之间的串扰来整合信号级联。
The protein tyrosine kinase c-Src is regulated by two intramolecular interactions. The repressed state is achieved through the interaction of the Src homology 2 (SH2) domain with the phosphorylated C-terminal tail and the association of the SH3 domain with a polyproline type II helix formed by the linker region between SH2 and the kinase domain. hnRNP K, the founding member of the KH domain protein family, is involved in chromatin remodeling, regulation of transcription, and translation of specific mRNAs and is a target in different signal transduction pathways. In particular, it functions as a specific activator and a substrate of the tyrosine kinase c-Src. Here we address the question how hnRNP K interacts with and activates c-Src. We define the proline residues in hnRNP K in the proline-rich motifs P2 (amino acids [aa] 285 to 297) and P3 (aa 303 to 318), which are necessary and sufficient for the specific activation of c-Src, and we dissect the amino acid sequence (aa 216 to 226) of hnRNP K that mediates a second interaction with c-Src. Our findings indicate that the interaction with c-Src and the activation of the kinase are separable functions of hnRNP K. hnRNP K acts as a scaffold protein that integrates signaling cascades by facilitating the cross talk between kinases and factors that mediate nucleic acid-directed processes.