Altered Protein Interactions of the Endogenous Interactome of PTPIP51 towards MAPK Signaling.
Altered Protein Interactions of the Endogenous Interactome of PTPIP51 towards MAPK Signaling.
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DOI：
10.3390/biom7030055
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发表时间：
2017-07-21
期刊：
影响因子：
5.5
通讯作者：
Wimmer M
中科院分区：
文献类型：
--
作者：
Brobeil A;Chehab R;Dietel E;Gattenlöhner S;Wimmer M
蛋白质之间的相互作用在细胞的正常功能和致癌过程中起着关键作用。在信号转导过程中，蛋白质之间的相互作用形成功能簇。为了阐明蛋白质酪氨酸磷酸酶相互作用蛋白51(PTPIP51)的蛋白质-蛋白质相互作用的精细校正，一种直接针对PTPIP51的小分子药物LDC-3现已问世。因此，LDC-3可以通过调节PTPIP51的结合能力来研究内源性相互作用组的调节。小干扰核糖核酸(SiRNA)实验表明，LDC-3诱导了PTPIP51结合能力的改变。LDC-3的应用取消了已知的PTPIP51调节磷酸化机制，从而显著改变了PTPIP51相关蛋白复合体的组装。用LDC-3处理人角质形成细胞(HaCaT细胞)后，PTPIP51内源性相互作用组的蛋白质-蛋白质相互作用谱发生改变。此外，LDC-3在由Raf-1和支架蛋白14-3-3组成的丝裂原活化蛋白激酶(MAPK)复合体中稳定PTPIP51，与PTPIP51的磷酸化状态无关。值得注意的是，在LDC-3处理下，PTP1B对PTPIP51的调节功能未能影响PTPIP51的相互作用特征，正如在HaCaT细胞系中所报道的那样。综上所述，LDC-3为在恶性细胞中直接调控PTPIP51提供了独特的机会，从而靶向潜在的信号转导通路，如MAPK级联反应。所提供的数据为PTPIP51蛋白相互作用的治疗潜力提供了关键的见解，因此是可能的靶向治疗方案的基础。
Protein–protein interactions play a pivotal role in normal cellular functions as well as in carcinogenesis. The protein–protein interactions form functional clusters during signal transduction. To elucidate the fine calibration of the protein–protein interactions of protein tyrosine phosphatase interacting protein 51 (PTPIP51) a small molecule drug, namely LDC-3, directly targeting PTPIP51 is now available. Therefore, LDC-3 allows for the studying of the regulation of the endogenous interactome by modulating PTPIP51 binding capacity. Small interfering ribonucleic acid (siRNA) experiments show that the modification in PTPIP51 binding capacity is induced by LDC-3. Application of LDC-3 annuls the known regulatory phosphorylation mechanisms for PTPIP51 and consequently, significantly alters the assembly of the PTPIP51 associated protein complexes. The treatment of human keratinocytes (HaCaT cells) with LDC-3 induces an altered protein–protein interaction profile of the endogenous interactome of PTPIP51. In addition, LDC-3 stabilizes PTPIP51 within a mitogen activated protein kinase (MAPK) complex composed of Raf-1 and the scaffold protein 14-3-3, independent of the phosphorylation status of PTPIP51. Of note, under LDC-3 treatment the regulatory function of the PTP1B on PTPIP51 fails to impact the PTPIP51 interaction characteristics, as reported for the HaCaT cell line. In summary, LDC-3 gives the unique opportunity to directly modulate PTPIP51 in malignant cells, thus targeting potential dysregulated signal transduction pathways such as the MAPK cascade. The provided data give critical insights in the therapeutic potential of PTPIP51 protein interactions and thus are basic for possible targeted therapy regimens.
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影响因子：
5.3
作者：
Koch P;Stenzinger A;Viard M;Märker D;Mayser P;Nilles M;Schreiner D;Steger K;Wimmer M
通讯作者：
Wimmer M
影响因子：
3.5
作者：
De Vos KJ;Mórotz GM;Stoica R;Tudor EL;Lau KF;Ackerley S;Warley A;Shaw CE;Miller CC
通讯作者：
Miller CC
影响因子：
2.3
作者：
Brobeil, Alexander;Graf, Michaela;Wimmer, Monika
通讯作者：
Wimmer, Monika
影响因子：
2.5
作者：
Koch, P.;Viard, M.;Wimmer, M.
通讯作者：
Wimmer, M.
影响因子：
7.2
作者：
Lv, B. F.;Yu, C. F.;Wang, L.
通讯作者：
Wang, L.