Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1

Yiguo Zhang, Yong Yeon Cho, Brandon L. Petersen, Feng Zhu, Zigang Dong

Research output: Contribution to journalReview article

24 Citations (Scopus)

Abstract

Phosphorylation at Ser727 in signal transducer and activator of transcription 1 (STAT1) is essential for its activation and signal transduction. However, the upstream kinases responsible for phosphorylating Ser727 are still elusive. Here, we provide evidence showing that UVA-induced mitogen-activated protein kinase (MAPK) signaling pathways lead to STAT1 Ser727 phosphorylation. Our experimental results show that UVA-induced Ser727 phosphorylation of STAT1 was, to different degrees, diminished by PD98059 and U0126, two specific inhibitors of MEKs, and SB202190 and PD169316, inhibitors of p38 kinase and c-Jun N-terminal kinases (JNKs), respectively. STAT1 phosphorylation was also blocked by a dominant negative mutant of p38β kinase or JNK1, JNK1- or JNK2-deficiency, or an N-terminal or C-terminal kinase-dead mutant of mitogen- and stress-activated protein kinase 1 (MSK1), a downstream kinase closer to p38 kinase and extracellular signal-regulated kinases (ERKs). In vitro kinase assays using the combined STAT1 proteins as substrates from immunoprecipitation and glutathione S-transferase pull down show that active ERK1, JNK1, p38 kinase, MEK1 and MSK1 stimulated phosphorylation of STAT1 (Ser727) indirectly through an unidentified factor or a downstream kinase. Overall, our data indicate that phosphorylation of STAT1 at Ser727 occurs through diverse MAPK cascades including MEK1, ERKs, p38 kinase, JNKs and MSK1 in the cellular response to UVA.

Original languageEnglish (US)
Pages (from-to)1165-1175
Number of pages11
JournalCarcinogenesis
Volume25
Issue number7
DOIs
StatePublished - Jul 1 2004

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STAT1 Transcription Factor
Phosphotransferases
Phosphorylation
Mitogen-Activated Protein Kinase 8
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinases
Replication Protein C
MAP Kinase Kinase 1
STAT Transcription Factors
MAP Kinase Kinase 4
mitogen and stress-activated protein kinase 1
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Glutathione Transferase
Immunoprecipitation
Signal Transduction

Cite this

Zhang, Y., Cho, Y. Y., Petersen, B. L., Zhu, F., & Dong, Z. (2004). Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1. Carcinogenesis, 25(7), 1165-1175. https://doi.org/10.1093/carcin/bgh115

Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1. / Zhang, Yiguo; Cho, Yong Yeon; Petersen, Brandon L.; Zhu, Feng; Dong, Zigang.

In: Carcinogenesis, Vol. 25, No. 7, 01.07.2004, p. 1165-1175.

Research output: Contribution to journalReview article

Zhang, Y, Cho, YY, Petersen, BL, Zhu, F & Dong, Z 2004, 'Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1', Carcinogenesis, vol. 25, no. 7, pp. 1165-1175. https://doi.org/10.1093/carcin/bgh115
Zhang, Yiguo ; Cho, Yong Yeon ; Petersen, Brandon L. ; Zhu, Feng ; Dong, Zigang. / Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1. In: Carcinogenesis. 2004 ; Vol. 25, No. 7. pp. 1165-1175.
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N2 - Phosphorylation at Ser727 in signal transducer and activator of transcription 1 (STAT1) is essential for its activation and signal transduction. However, the upstream kinases responsible for phosphorylating Ser727 are still elusive. Here, we provide evidence showing that UVA-induced mitogen-activated protein kinase (MAPK) signaling pathways lead to STAT1 Ser727 phosphorylation. Our experimental results show that UVA-induced Ser727 phosphorylation of STAT1 was, to different degrees, diminished by PD98059 and U0126, two specific inhibitors of MEKs, and SB202190 and PD169316, inhibitors of p38 kinase and c-Jun N-terminal kinases (JNKs), respectively. STAT1 phosphorylation was also blocked by a dominant negative mutant of p38β kinase or JNK1, JNK1- or JNK2-deficiency, or an N-terminal or C-terminal kinase-dead mutant of mitogen- and stress-activated protein kinase 1 (MSK1), a downstream kinase closer to p38 kinase and extracellular signal-regulated kinases (ERKs). In vitro kinase assays using the combined STAT1 proteins as substrates from immunoprecipitation and glutathione S-transferase pull down show that active ERK1, JNK1, p38 kinase, MEK1 and MSK1 stimulated phosphorylation of STAT1 (Ser727) indirectly through an unidentified factor or a downstream kinase. Overall, our data indicate that phosphorylation of STAT1 at Ser727 occurs through diverse MAPK cascades including MEK1, ERKs, p38 kinase, JNKs and MSK1 in the cellular response to UVA.

AB - Phosphorylation at Ser727 in signal transducer and activator of transcription 1 (STAT1) is essential for its activation and signal transduction. However, the upstream kinases responsible for phosphorylating Ser727 are still elusive. Here, we provide evidence showing that UVA-induced mitogen-activated protein kinase (MAPK) signaling pathways lead to STAT1 Ser727 phosphorylation. Our experimental results show that UVA-induced Ser727 phosphorylation of STAT1 was, to different degrees, diminished by PD98059 and U0126, two specific inhibitors of MEKs, and SB202190 and PD169316, inhibitors of p38 kinase and c-Jun N-terminal kinases (JNKs), respectively. STAT1 phosphorylation was also blocked by a dominant negative mutant of p38β kinase or JNK1, JNK1- or JNK2-deficiency, or an N-terminal or C-terminal kinase-dead mutant of mitogen- and stress-activated protein kinase 1 (MSK1), a downstream kinase closer to p38 kinase and extracellular signal-regulated kinases (ERKs). In vitro kinase assays using the combined STAT1 proteins as substrates from immunoprecipitation and glutathione S-transferase pull down show that active ERK1, JNK1, p38 kinase, MEK1 and MSK1 stimulated phosphorylation of STAT1 (Ser727) indirectly through an unidentified factor or a downstream kinase. Overall, our data indicate that phosphorylation of STAT1 at Ser727 occurs through diverse MAPK cascades including MEK1, ERKs, p38 kinase, JNKs and MSK1 in the cellular response to UVA.

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