Identification and functional analysis of SOX10 phosphorylation sites in melanoma.
Identification and functional analysis of SOX10 phosphorylation sites in melanoma.
复制标题
DOI：
10.1371/journal.pone.0190834
复制
发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Pavan WJ
中科院分区：
文献类型：
--
作者：
Cronin JC;Loftus SK;Baxter LL;Swatkoski S;Gucek M;Pavan WJ
转录因子 SOX10 在脊椎动物神经嵴发育中发挥重要作用，包括黑素细胞谱系的建立和维持。 SOX10 在黑色素瘤中也高表达，并且 SOX10 表达随着肿瘤进展而增加。黑色素瘤细胞中 SOX10 的抑制会激活 TGF-β 信号传导，并可促进对 BRAF 和 MEK 抑制剂的耐药性。由于大多数黑色素瘤患者对 BRAF/MEK 抑制剂具有耐药性，因此迫切需要评估介导耐药性的潜在生物学并确定组合治疗方法的新靶点。之前，我们证明 SOX10 蛋白是肿瘤发生、维持和存活所必需的。在这里，我们提供的数据支持磷酸化是黑色素瘤细胞用来严格调节 SOX10 表达的机制。质谱法鉴定出 SOX10 中包含的 8 个磷酸化位点，其中 3 个（S24、S45 和 T240）根据其在预测的 MAPK/CDK 结合基序中的位置被选择用于进一步分析。在这些磷酸化位点产生 SOX10 突变，以评估它们对黑色素瘤细胞中 SOX10 蛋白功能的影响，包括靶启动子的转录激活、亚细胞定位和稳定性。这些数据进一步加深了我们对 SOX10 蛋白调节的理解，并为识别调节黑色素瘤中 SOX10 蛋白水平的分子途径提供了关键信息，最终目标是发现新的靶标，为黑色素瘤患者提供更有效的组合治疗方法。
The transcription factor SOX10 plays an important role in vertebrate neural crest development, including the establishment and maintenance of the melanocyte lineage. SOX10 is also highly expressed in melanoma tumors, and SOX10 expression increases with tumor progression. The suppression of SOX10 in melanoma cells activates TGF-β signaling and can promote resistance to BRAF and MEK inhibitors. Since resistance to BRAF/MEK inhibitors is seen in the majority of melanoma patients, there is an immediate need to assess the underlying biology that mediates resistance and to identify new targets for combinatorial therapeutic approaches. Previously, we demonstrated that SOX10 protein is required for tumor initiation, maintenance and survival. Here, we present data that support phosphorylation as a mechanism employed by melanoma cells to tightly regulate SOX10 expression. Mass spectrometry identified eight phosphorylation sites contained within SOX10, three of which (S24, S45 and T240) were selected for further analysis based on their location within predicted MAPK/CDK binding motifs. SOX10 mutations were generated at these phosphorylation sites to assess their impact on SOX10 protein function in melanoma cells, including transcriptional activation on target promoters, subcellular localization, and stability. These data further our understanding of SOX10 protein regulation and provide critical information for identification of molecular pathways that modulate SOX10 protein levels in melanoma, with the ultimate goal of discovering novel targets for more effective combinatorial therapeutic approaches for melanoma patients.
登录
查看更多内容
唾液腺样囊性和乳腺基底癌中的诊断SOX10基因特征。
影响因子：
8.8
作者：
Ivanov SV;Panaccione A;Nonaka D;Prasad ML;Boyd KL;Brown B;Guo Y;Sewell A;Yarbrough WG
通讯作者：
Yarbrough WG
影响因子：
4.3
作者：
Cronin JC;Wunderlich J;Loftus SK;Prickett TD;Wei X;Ridd K;Vemula S;Burrell AS;Agrawal NS;Lin JC;Banister CE;Buckhaults P;Rosenberg SA;Bastian BC;Pavan WJ;Samuels Y
通讯作者：
Samuels Y
影响因子：
5.3
作者：
BENTLEY, NJ;EISEN, T;GODING, CR
通讯作者：
GODING, CR
通过相互关联的翻译后修饰调节转录因子活性。
影响因子：
13.8
作者：
Filtz, Theresa M.;Vogel, Walter K.;Leid, Mark
通讯作者：
Leid, Mark
影响因子：
11.2
作者：
Cronin JC;Watkins-Chow DE;Incao A;Hasskamp JH;Schönewolf N;Aoude LG;Hayward NK;Bastian BC;Dummer R;Loftus SK;Pavan WJ
通讯作者：
Pavan WJ