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蛋白磷酸酶2Cδ/Wip1调节银屑病皮损中磷酸化p90RSK2的活性。

Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin.

作者信息

Rasmussen Mads K, Nielsen Jakob, Kjellerup Rasmus B, Andersen Stine M, Rittig Anne H, Johansen Claus, Iversen Lars, Gesser Borbala

机构信息

Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark.

出版信息

J Inflamm Res. 2017 Dec 15;10:169-180. doi: 10.2147/JIR.S152869. eCollection 2017.

DOI:10.2147/JIR.S152869
PMID:29290690
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5735993/
Abstract

OBJECTIVES

P90 ribosomal S6 kinase (RSK) 1 and 2 are serine/threonine protein kinases believed to mediate proliferation and apoptosis via the extracellular signal-regulated kinases (ERK1/2) signaling pathway. Macrophage migration inhibitory factor (MIF) and epidermal growth factor (EGF) are activators of this pathway and are elevated in the serum of patients with psoriasis compared with healthy controls. Studies on COS-7 cell cultures have shown that protein phosphatase 2Cδ (PP2Cδ) decreases the activity of RSK2 following EGF stimulation. We therefore hypothesize that PP2Cδ regulates RSK2 activity in psoriasis.

METHODS

In paired biopsies from nonlesional (NL) and lesional (L) skins, we analyzed the level of RSK1, 2 phosphorylation and the expression of PP2Cδ isoforms, integrin-linked kinase-associated serine/threonine phosphatase (ILKAP) and wild-type p53-induced phosphatase 1 (Wip1) by Western blotting, immunofluorescence and coimmunoprecipitation with monoclonal antibody for RSK2. The induction of Wip1 by MIF or EGF was studied in cultured normal human keratinocytes.

RESULTS

The protein level of RSK1, 2 phosphorylated at T573/T577 was significantly increased in L compared with NL psoriatic skin, while phosphorylation at S380/S386 was reduced in L compared with NL psoriatic skin when assayed by Western blotting and immunofluorescence microscopy. ILKAP expression was significantly higher in L than in NL skin, whereas Wip1 was expressed in similar amounts but showed increased coimmunoprecipitation with RSK2 in L compared with NL psoriatic skin. In cultured normal human keratinocytes stimulated with MIF, Wip1 phosphorylation and Wip1 expression were increased after 24 hours, but not when costimulated with dimethyl fumarate (DMF). The increased coimmunoprecipitation of Wip1 with RSK2 was significantly induced by EGF or MIF activation at 24 hours and could be significantly inhibited by DMF or the ERK1/2 inhibitor PD98059.

CONCLUSION

The complex formation of Wip1 with RSK2 indicates a direct interaction reducing P-RSK2 (S386) activation in L skin and indicates that Wip1 has a role in the pathogenesis of psoriasis.

摘要

目的

P90核糖体S6激酶（RSK）1和2是丝氨酸/苏氨酸蛋白激酶，被认为可通过细胞外信号调节激酶（ERK1/2）信号通路介导细胞增殖和凋亡。巨噬细胞移动抑制因子（MIF）和表皮生长因子（EGF）是该通路的激活剂，与健康对照相比，银屑病患者血清中其水平升高。对COS-7细胞培养的研究表明，蛋白磷酸酶2Cδ（PP2Cδ）在EGF刺激后会降低RSK2的活性。因此，我们推测PP2Cδ在银屑病中调节RSK2的活性。

方法

在取自非皮损（NL）和皮损（L）皮肤的配对活检样本中，我们通过蛋白质印迹法、免疫荧光法以及用针对RSK2的单克隆抗体进行免疫共沉淀，分析了RSK1、2的磷酸化水平以及PP2Cδ亚型、整合素连接激酶相关丝氨酸/苏氨酸磷酸酶（ILKAP）和野生型p53诱导的磷酸酶1（Wip1）的表达。在培养的正常人角质形成细胞中研究了MIF或EGF对Wip1的诱导作用。

结果

通过蛋白质印迹法和免疫荧光显微镜检测，与NL银屑病皮肤相比，L银屑病皮肤中T573/T577位点磷酸化的RSK1、2的蛋白水平显著升高，而S380/S386位点的磷酸化水平在L中较NL银屑病皮肤降低。ILKAP在L中的表达明显高于NL皮肤，而Wip1的表达量相似，但与NL银屑病皮肤相比，其在L中与RSK2的免疫共沉淀增加。在用MIF刺激的培养正常人角质形成细胞中，24小时后Wip1磷酸化和Wip1表达增加，但与富马酸二甲酯（DMF）共刺激时则不然。24小时时，EGF或MIF激活可显著诱导Wip1与RSK2的免疫共沉淀增加，且可被DMF或ERK1/2抑制剂PD98059显著抑制。

结论

Wip1与RSK2形成复合物表明存在直接相互作用，可降低L皮肤中P-RSK2（S386）的活性，这表明Wip1在银屑病发病机制中起作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b606/5735993/6718e3a68a66/jir-10-169Fig8.jpg
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