P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b

Metastatic melanoma is the most aggressive type of skin cancer. Previously, we identified the plasma membrane Ca<sup>2+</sup> pump isoform 4b (PMCA4b or <i>ATP2B4</i>) as a putative metastasis suppressor in BRAF mutant melanoma cells. Metastasis suppressors are often downregu...

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Main Authors: Randa Naffa, Lisa Vogel, Luca Hegedűs, Katalin Pászty, Sarolta Tóth, Kornélia Kelemen, Neha Singh, Attila Reményi, Enikő Kállay, Mihály Cserepes, József Tóvári, Michael Grusch, Ágnes Enyedi
Format: Article
Language:English
Published: MDPI AG 2020-05-01
Series:Cells
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Online Access:https://www.mdpi.com/2073-4409/9/5/1209
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spelling doaj-94fa8bca835147719b519ff54ca792392020-11-25T02:05:55ZengMDPI AGCells2073-44092020-05-0191209120910.3390/cells9051209P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4bRanda Naffa0Lisa Vogel1Luca Hegedűs2Katalin Pászty3Sarolta Tóth4Kornélia Kelemen5Neha Singh6Attila Reményi7Enikő Kállay8Mihály Cserepes9József Tóvári10Michael Grusch11Ágnes Enyedi122nd Institute of Pathology, Semmelweis University, H-1091 Budapest, HungaryInstitute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna A-1090, AustriaDepartment of Thoracic Surgery, Ruhrlandklinik, University Clinic, D-45239 Essen, GermanyDepartment of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, HungaryDepartment of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, H-1117 Budapest, Hungary2nd Institute of Pathology, Semmelweis University, H-1091 Budapest, HungaryInstitute of Organic Chemistry, Research Centre for Natural Sciences, HAS, H-1117 Budapest, HungaryInstitute of Organic Chemistry, Research Centre for Natural Sciences, HAS, H-1117 Budapest, HungaryInstitute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, AustriaNational Institute of Oncology, Department of Experimental Pharmacology, H-1122 Budapest, HungaryNational Institute of Oncology, Department of Experimental Pharmacology, H-1122 Budapest, HungaryInstitute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna A-1090, Austria2nd Institute of Pathology, Semmelweis University, H-1091 Budapest, HungaryMetastatic melanoma is the most aggressive type of skin cancer. Previously, we identified the plasma membrane Ca<sup>2+</sup> pump isoform 4b (PMCA4b or <i>ATP2B4</i>) as a putative metastasis suppressor in BRAF mutant melanoma cells. Metastasis suppressors are often downregulated in cancer, therefore, it is important to identify the pathways involved in their degradation. Here, we studied the role of p38 MAPK in PMCA4b degradation and its effect on melanoma metastasis. We found that activation of p38 MAPK induces internalization and subsequent degradation of PMCA4b through the endo/lysosomal system that contributes to the low PMCA4b steady-state protein level of BRAF mutant melanoma cells. Moreover, BRAF wild type cell models including a doxycycline-inducible HEK cell system revealed that p38 MAPK is a universal modulator of PMCA4b endocytosis. Inhibition of the p38 MAPK pathway markedly reduced migration, colony formation and metastatic activity of BRAF mutant cells in vitro partially through an increase in PMCA4b and a decrease in β4 integrin abundance. In conclusion, our data suggest that the p38 MAPK pathway plays a key role in PMCA4b degradation and inhibition of this pathway—by increasing the stability of PMCA4b—may provide a potential therapeutic target for inhibition of melanoma progression and metastasis.https://www.mdpi.com/2073-4409/9/5/1209plasma membrane Ca<sup>2+</sup>ATPase isoform 4bp38 mitogen-activated protein kinase (MAPK)endocytosiscalcium signalingBRAF mutant melanomametastasis
collection DOAJ
language English
format Article
sources DOAJ
author Randa Naffa
Lisa Vogel
Luca Hegedűs
Katalin Pászty
Sarolta Tóth
Kornélia Kelemen
Neha Singh
Attila Reményi
Enikő Kállay
Mihály Cserepes
József Tóvári
Michael Grusch
Ágnes Enyedi
spellingShingle Randa Naffa
Lisa Vogel
Luca Hegedűs
Katalin Pászty
Sarolta Tóth
Kornélia Kelemen
Neha Singh
Attila Reményi
Enikő Kállay
Mihály Cserepes
József Tóvári
Michael Grusch
Ágnes Enyedi
P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b
Cells
plasma membrane Ca<sup>2+</sup>ATPase isoform 4b
p38 mitogen-activated protein kinase (MAPK)
endocytosis
calcium signaling
BRAF mutant melanoma
metastasis
author_facet Randa Naffa
Lisa Vogel
Luca Hegedűs
Katalin Pászty
Sarolta Tóth
Kornélia Kelemen
Neha Singh
Attila Reményi
Enikő Kállay
Mihály Cserepes
József Tóvári
Michael Grusch
Ágnes Enyedi
author_sort Randa Naffa
title P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b
title_short P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b
title_full P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b
title_fullStr P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b
title_full_unstemmed P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b
title_sort p38 mapk promotes migration and metastatic activity of braf mutant melanoma cells by inducing degradation of pmca4b
publisher MDPI AG
series Cells
issn 2073-4409
publishDate 2020-05-01
description Metastatic melanoma is the most aggressive type of skin cancer. Previously, we identified the plasma membrane Ca<sup>2+</sup> pump isoform 4b (PMCA4b or <i>ATP2B4</i>) as a putative metastasis suppressor in BRAF mutant melanoma cells. Metastasis suppressors are often downregulated in cancer, therefore, it is important to identify the pathways involved in their degradation. Here, we studied the role of p38 MAPK in PMCA4b degradation and its effect on melanoma metastasis. We found that activation of p38 MAPK induces internalization and subsequent degradation of PMCA4b through the endo/lysosomal system that contributes to the low PMCA4b steady-state protein level of BRAF mutant melanoma cells. Moreover, BRAF wild type cell models including a doxycycline-inducible HEK cell system revealed that p38 MAPK is a universal modulator of PMCA4b endocytosis. Inhibition of the p38 MAPK pathway markedly reduced migration, colony formation and metastatic activity of BRAF mutant cells in vitro partially through an increase in PMCA4b and a decrease in β4 integrin abundance. In conclusion, our data suggest that the p38 MAPK pathway plays a key role in PMCA4b degradation and inhibition of this pathway—by increasing the stability of PMCA4b—may provide a potential therapeutic target for inhibition of melanoma progression and metastasis.
topic plasma membrane Ca<sup>2+</sup>ATPase isoform 4b
p38 mitogen-activated protein kinase (MAPK)
endocytosis
calcium signaling
BRAF mutant melanoma
metastasis
url https://www.mdpi.com/2073-4409/9/5/1209
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