Identification of a DYRK1A-mediated phosphorylation site within the nuclear localization sequence of the hedgehog transcription factor GLI1.
Identification of a DYRK1A-mediated phosphorylation site within the nuclear localization sequence of the hedgehog transcription factor GLI1.
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DOI：
10.1016/j.bbrc.2017.07.107
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发表时间：
2017-09-23
影响因子：
3.1
通讯作者：
Williams KP
中科院分区：
文献类型：
--
作者：
Ehe BK;Lamson DR;Tarpley M;Onyenwoke RU;Graves LM;Williams KP
GLI 1是Hedgehog（Hh）信号通路的关键下游转录效应子，其参与促进胚胎发育中的细胞生长、分化和组织形成。GLI 1过度激活及其核定位也与许多癌症的侵袭性增加有关。DYRK 1A（dual-specificity tyrosine-regulated kinase 1A，双特异性酪氨酸调节激酶1A）能够磷酸化GLI 1，促进GLI 1的核定位及其转录活性。利用重组人GLI 1和DYRK 1A蛋白和磷酸肽质谱，我们证明了GLI 1是磷酸化DYRK 1A在Ser 408，磷酸化位点，福尔斯内的推定的核定位序列（NLS）的GLI 1表明可能的机制作用，在调节其易位。此外，我们发现，GLI 1上的Ser 408位点在选择性DYRK 1A抑制剂去氢骆驼蓬碱的存在下不被磷酸化。本文描述的数据提供了在其NLS内GLI 1上DYRK 1A介导的磷酸化位点的首次鉴定，并且可以作为进一步理解Hh信号转导调节的有价值的机制。
GLI1 is a key downstream transcription effector of the Hedgehog (Hh) signaling pathway that is involved in promoting cell growth, differentiation and tissue patterning in embryonic development. GLI1 over-activation and its nuclear localization has also been linked to the increased aggressiveness of a number of cancers. It has previously been demonstrated that DYRK1A (dual-specificity tyrosine-regulated kinase 1A) can phosphorylate GLI1 and promote GLI1 nuclear localization and its transcriptional activity. Utilizing recombinant human GLI1 and DYRK1A proteins and phospho-peptide mass spectrometry, we demonstrated that GLI1 is phosphorylated by DYRK1A at Ser408, a phospho-site that falls within the putative nuclear localization sequence (NLS) of GLI1 suggesting a possible mechanistic role in modulating its translocation. Further, we showed that the Ser408 site on GLI1 was not phosphorylated in the presence of the selective DYRK1A inhibitor harmine. The data described herein provide the first identification of a DYRK1A-mediated site of phosphorylation on GLI1 within its NLS and may serve as a valuable mechanism for further understanding Hh signaling modulation.
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