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Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion

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Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. / Eerola, Sini K.; Santio, Niina M.; Rinne, Sanni; Kouvonen, Petri; Corthals, Garry L.; Scaravilli, Mauro; Scala, Giovanni; Serra, Angela; Greco, Dario; Ruusuvuori, Pekka; Latonen, Leena; Rainio, Eeva Marja; Visakorpi, Tapio; Koskinen, Päivi J.

In: CELL COMMUNICATION AND SIGNALING, Vol. 17, No. 1, 148, 15.11.2019.

Research output: Contribution to journalArticleScientificpeer-review

Harvard

Eerola, SK, Santio, NM, Rinne, S, Kouvonen, P, Corthals, GL, Scaravilli, M, Scala, G, Serra, A, Greco, D, Ruusuvuori, P, Latonen, L, Rainio, EM, Visakorpi, T & Koskinen, PJ 2019, 'Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion', CELL COMMUNICATION AND SIGNALING, vol. 17, no. 1, 148. https://doi.org/10.1186/s12964-019-0463-y

APA

Eerola, S. K., Santio, N. M., Rinne, S., Kouvonen, P., Corthals, G. L., Scaravilli, M., ... Koskinen, P. J. (2019). Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. CELL COMMUNICATION AND SIGNALING, 17(1), [148]. https://doi.org/10.1186/s12964-019-0463-y

Vancouver

Eerola SK, Santio NM, Rinne S, Kouvonen P, Corthals GL, Scaravilli M et al. Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. CELL COMMUNICATION AND SIGNALING. 2019 Nov 15;17(1). 148. https://doi.org/10.1186/s12964-019-0463-y

Author

Eerola, Sini K. ; Santio, Niina M. ; Rinne, Sanni ; Kouvonen, Petri ; Corthals, Garry L. ; Scaravilli, Mauro ; Scala, Giovanni ; Serra, Angela ; Greco, Dario ; Ruusuvuori, Pekka ; Latonen, Leena ; Rainio, Eeva Marja ; Visakorpi, Tapio ; Koskinen, Päivi J. / Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. In: CELL COMMUNICATION AND SIGNALING. 2019 ; Vol. 17, No. 1.

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@article{299ee07a5f8243d684b66078c43e6d82,
title = "Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion",
abstract = "Background: Progression of prostate cancer from benign local tumors to metastatic carcinomas is a multistep process. Here we have investigated the signaling pathways that support migration and invasion of prostate cancer cells, focusing on the role of the NFATC1 transcription factor and its post-translational modifications. We have previously identified NFATC1 as a substrate for the PIM1 kinase and shown that PIM1-dependent phosphorylation increases NFATC1 activity without affecting its subcellular localization. Both PIM kinases and NFATC1 have been reported to promote cancer cell migration, invasion and angiogenesis, but it has remained unclear whether the effects of NFATC1 are phosphorylation-dependent and which downstream targets are involved. Methods: We used mass spectrometry to identify PIM1 phosphorylation target sites in NFATC1, and analysed their functional roles in three prostate cancer cell lines by comparing phosphodeficient mutants to wild-type NFATC1. We used luciferase assays to determine effects of phosphorylation on NFAT-dependent transcriptional activity, and migration and invasion assays to evaluate effects on cell motility. We also performed a microarray analysis to identify novel PIM1/NFATC1 targets, and validated one of them with both cellular expression analyses and in silico in clinical prostate cancer data sets. Results: Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. We observed that also PIM2 and PIM3 can phosphorylate NFATC1, and identified several novel putative PIM1/NFATC1 target genes. These include the ITGA5 integrin, which is differentially expressed in the presence of wild-type versus phosphorylation-deficient NFATC1, and which is coexpressed with PIM1 and NFATC1 in clinical prostate cancer specimens. Conclusions: Based on our data, phosphorylation of PIM1 target sites stimulates NFATC1 activity and enhances its ability to promote prostate cancer cell migration and invasion. Therefore, inhibition of the interplay between PIM kinases and NFATC1 may have therapeutic implications for patients with metastatic forms of cancer.",
keywords = "Cell motility, Metastatic carcinoma, NFATC1, PIM kinases, Prostate cancer",
author = "Eerola, {Sini K.} and Santio, {Niina M.} and Sanni Rinne and Petri Kouvonen and Corthals, {Garry L.} and Mauro Scaravilli and Giovanni Scala and Angela Serra and Dario Greco and Pekka Ruusuvuori and Leena Latonen and Rainio, {Eeva Marja} and Tapio Visakorpi and Koskinen, {P{\"a}ivi J.}",
year = "2019",
month = "11",
day = "15",
doi = "10.1186/s12964-019-0463-y",
language = "English",
volume = "17",
journal = "CELL COMMUNICATION AND SIGNALING",
issn = "1478-811X",
publisher = "Signal Transduction Society",
number = "1",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion

AU - Eerola, Sini K.

AU - Santio, Niina M.

AU - Rinne, Sanni

AU - Kouvonen, Petri

AU - Corthals, Garry L.

AU - Scaravilli, Mauro

AU - Scala, Giovanni

AU - Serra, Angela

AU - Greco, Dario

AU - Ruusuvuori, Pekka

AU - Latonen, Leena

AU - Rainio, Eeva Marja

AU - Visakorpi, Tapio

AU - Koskinen, Päivi J.

PY - 2019/11/15

Y1 - 2019/11/15

N2 - Background: Progression of prostate cancer from benign local tumors to metastatic carcinomas is a multistep process. Here we have investigated the signaling pathways that support migration and invasion of prostate cancer cells, focusing on the role of the NFATC1 transcription factor and its post-translational modifications. We have previously identified NFATC1 as a substrate for the PIM1 kinase and shown that PIM1-dependent phosphorylation increases NFATC1 activity without affecting its subcellular localization. Both PIM kinases and NFATC1 have been reported to promote cancer cell migration, invasion and angiogenesis, but it has remained unclear whether the effects of NFATC1 are phosphorylation-dependent and which downstream targets are involved. Methods: We used mass spectrometry to identify PIM1 phosphorylation target sites in NFATC1, and analysed their functional roles in three prostate cancer cell lines by comparing phosphodeficient mutants to wild-type NFATC1. We used luciferase assays to determine effects of phosphorylation on NFAT-dependent transcriptional activity, and migration and invasion assays to evaluate effects on cell motility. We also performed a microarray analysis to identify novel PIM1/NFATC1 targets, and validated one of them with both cellular expression analyses and in silico in clinical prostate cancer data sets. Results: Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. We observed that also PIM2 and PIM3 can phosphorylate NFATC1, and identified several novel putative PIM1/NFATC1 target genes. These include the ITGA5 integrin, which is differentially expressed in the presence of wild-type versus phosphorylation-deficient NFATC1, and which is coexpressed with PIM1 and NFATC1 in clinical prostate cancer specimens. Conclusions: Based on our data, phosphorylation of PIM1 target sites stimulates NFATC1 activity and enhances its ability to promote prostate cancer cell migration and invasion. Therefore, inhibition of the interplay between PIM kinases and NFATC1 may have therapeutic implications for patients with metastatic forms of cancer.

AB - Background: Progression of prostate cancer from benign local tumors to metastatic carcinomas is a multistep process. Here we have investigated the signaling pathways that support migration and invasion of prostate cancer cells, focusing on the role of the NFATC1 transcription factor and its post-translational modifications. We have previously identified NFATC1 as a substrate for the PIM1 kinase and shown that PIM1-dependent phosphorylation increases NFATC1 activity without affecting its subcellular localization. Both PIM kinases and NFATC1 have been reported to promote cancer cell migration, invasion and angiogenesis, but it has remained unclear whether the effects of NFATC1 are phosphorylation-dependent and which downstream targets are involved. Methods: We used mass spectrometry to identify PIM1 phosphorylation target sites in NFATC1, and analysed their functional roles in three prostate cancer cell lines by comparing phosphodeficient mutants to wild-type NFATC1. We used luciferase assays to determine effects of phosphorylation on NFAT-dependent transcriptional activity, and migration and invasion assays to evaluate effects on cell motility. We also performed a microarray analysis to identify novel PIM1/NFATC1 targets, and validated one of them with both cellular expression analyses and in silico in clinical prostate cancer data sets. Results: Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. We observed that also PIM2 and PIM3 can phosphorylate NFATC1, and identified several novel putative PIM1/NFATC1 target genes. These include the ITGA5 integrin, which is differentially expressed in the presence of wild-type versus phosphorylation-deficient NFATC1, and which is coexpressed with PIM1 and NFATC1 in clinical prostate cancer specimens. Conclusions: Based on our data, phosphorylation of PIM1 target sites stimulates NFATC1 activity and enhances its ability to promote prostate cancer cell migration and invasion. Therefore, inhibition of the interplay between PIM kinases and NFATC1 may have therapeutic implications for patients with metastatic forms of cancer.

KW - Cell motility

KW - Metastatic carcinoma

KW - NFATC1

KW - PIM kinases

KW - Prostate cancer

U2 - 10.1186/s12964-019-0463-y

DO - 10.1186/s12964-019-0463-y

M3 - Article

VL - 17

JO - CELL COMMUNICATION AND SIGNALING

JF - CELL COMMUNICATION AND SIGNALING

SN - 1478-811X

IS - 1

M1 - 148

ER -