Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin
Mads K Rasmussen, Jakob Nielsen, Rasmus B Kjellerup, Stine M Andersen, Anne H Rittig, Claus Johansen, Lars Iversen, Borbala Gesser Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark Objectives: P90 ribosomal S6 kinase...
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Dove Medical Press
2017
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oai:doaj.org-article:5f89346603c64faaa94b4d0d76381ed62021-12-02T03:01:24ZProtein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin1178-7031https://doaj.org/article/5f89346603c64faaa94b4d0d76381ed62017-12-01T00:00:00Zhttps://www.dovepress.com/protein-phosphatase-2cdeltawip1-regulates-phospho-p90rsk2-activity-in--peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Mads K Rasmussen, Jakob Nielsen, Rasmus B Kjellerup, Stine M Andersen, Anne H Rittig, Claus Johansen, Lars Iversen, Borbala Gesser Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark 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. Keywords: P90 RSK1, 2, EGF, MIF, PP2Cδ/ILKAP, PP2Cδ/Wip1Rasmussen MKNielsen JKjellerup RBAndersen SMRittig AHJohansen CIversen LGesser BDove Medical PressarticleP90 RSK12EGFMIFPP2Cδ/ILKAPPP2Cδ/Wip1PathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 10, Pp 169-180 (2017) |
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DOAJ |
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EN |
| topic |
P90 RSK1 2 EGF MIF PP2Cδ/ILKAP PP2Cδ/Wip1 Pathology RB1-214 Therapeutics. Pharmacology RM1-950 |
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P90 RSK1 2 EGF MIF PP2Cδ/ILKAP PP2Cδ/Wip1 Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Rasmussen MK Nielsen J Kjellerup RB Andersen SM Rittig AH Johansen C Iversen L Gesser B Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin |
| description |
Mads K Rasmussen, Jakob Nielsen, Rasmus B Kjellerup, Stine M Andersen, Anne H Rittig, Claus Johansen, Lars Iversen, Borbala Gesser Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark 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. Keywords: P90 RSK1, 2, EGF, MIF, PP2Cδ/ILKAP, PP2Cδ/Wip1 |
| format |
article |
| author |
Rasmussen MK Nielsen J Kjellerup RB Andersen SM Rittig AH Johansen C Iversen L Gesser B |
| author_facet |
Rasmussen MK Nielsen J Kjellerup RB Andersen SM Rittig AH Johansen C Iversen L Gesser B |
| author_sort |
Rasmussen MK |
| title |
Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin |
| title_short |
Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin |
| title_full |
Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin |
| title_fullStr |
Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin |
| title_full_unstemmed |
Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin |
| title_sort |
protein phosphatase 2cδ/wip1 regulates phospho-p90rsk2 activity in lesional psoriatic skin |
| publisher |
Dove Medical Press |
| publishDate |
2017 |
| url |
https://doaj.org/article/5f89346603c64faaa94b4d0d76381ed6 |
| work_keys_str_mv |
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| _version_ |
1718401987006955520 |