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Cited by 83Protein Tyrosine PhosphatasesCytokine Signaling Pathways and InteractionsProtein Kinase Regulation and GTPase Signaling

Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation

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Kim, Dae Joon, Tremblay, Michel L., DiGiovanni, John·2010·PLoS ONE
DOI 10.1371/journal.pone.0010290PMC PMC2858656
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Abstract

Stat3 is initially dephosphorylated in murine keratinocytes in response to UVB irradiation. Treatment with Na(3)VO(4) desensitized keratinocytes to UVB-induced apoptosis with the recovery of phosphorylated Stat3 protein levels, implying that a protein tyrosine phosphatase (PTP) is involved in this mechanism. In the current work, we report that three PTPs including TC45 (the nuclear form of TC-PTP), SHP1, and SHP2 are involved in this rapid dephosphorylation of Stat3 in keratinocytes induced by UVB irradiation. Dephosphorylation of Stat3 was increased rapidly after UVB irradiation of cultured keratinocytes. Knockdown of TC-PTP, SHP1, or SHP2 using RNAi showed that these PTPs are likely responsible for most of the rapid Stat3 dephosphorylation observed following UVB irradiation. The level of phosphorylated Stat3 was significantly higher in keratinocytes transfected with TC-PTP, SHP1, or SHP2 siRNA in the presence or absence of UVB compared with keratinocytes transfected with control siRNA. TC45 was mainly localized in the cytoplasm of keratinocytes and translocated from cytoplasm to nucleus upon UVB irradiation. Stat3 dephosphorylation was associated with nuclear translocation of TC45. Further studies revealed that knockdown of all three phosphatases, using RNAi, prevented the rapid dephosphorylation of Stat3 following UVB irradiation. In mouse epidermis, the level of phosphorylated Stat3 was initially decreased, followed by a significant increase at later time points after UVB exposure. The levels of Stat3 target genes, such as cyclin D1 and c-Myc, followed the changes in activated Stat3 in response to UVB irradiation. Collectively, these results suggest that three phosphatases, TC45, SHP1, and SHP2, are primarily responsible for UVB-mediated Stat3 dephosphorylation and may serve as part of an initial protective mechanism against UV skin carcinogenesis.

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  • The combined knockdown of TC45 in combination with the cytoplasmic tyrosine phosphatases SHP1 and SHP2 has been shown to be insufficient in prolonging STAT3 phosphorylation.

    “the combined knockdown of TC45 in combination with the cytoplasmic tyrosine phosphatases SHP1 (SH2 domain-containing protein tyrosine phosphatase 1) [35,36] and SHP2 [37,38] has also been shown more recently to be insufficient in prolonging STAT3 phosphorylation [39].”

    From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [39]

    The Results section (Figure 6; page unavailable) reports that combined knockdown of TC-PTP, SHP1, and SHP2 increased phosphorylated Stat3 and reduced its dephosphorylation after UVB irradiation—the opposite of saying the knockdown was insufficient to prolong phosphorylation. The Discussion notes that some dephosphorylation still occurred, but does not say the knockdown had no effect. (LLM, conf=0.88)

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Authors
Kim, D. J., Tremblay, M. L., & DiGiovanni, J.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • McGill University (CA)
Corresponding author
  • Kim, Dae Joon
  • DiGiovanni, John
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-04-22
Volume
5
Issue
4
Pages
e10290
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0010290
PMC
PMC2858656
OpenAlex
W2049569756
Cited by
83
References
4
Citations by year
2025: 3 · 2024: 4 · 2022: 4 · 2021: 13 · 2020: 4 · 2019: 5 · 2018: 8 · 2017: 8 · 2016: 5 · 2015: 5 · 2014: 8 · 2013: 4 · 2012: 9
FWCI
2.09
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Cancer Institute (CA-16672, CA-105345, U01CA105345, CA76520, R01CA076520, P30CA016672)
  • National Institute of Environmental Health Sciences (#ES07784, P30ES007784)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
STAT3 dephosphorylation, protein tyrosine phosphatase, TCPTP, SHP-1, SHP2, keratinocytes, UVB irradiation, nuclear translocation, UV-induced apoptosis, cyclin D1, c-Myc, epidermis
MeSH terms
Animals, Cells, Cultured, Phosphorylation, Ultraviolet Rays, Keratinocytes, Apoptosis, RNA, Small Interfering, STAT3 Transcription Factor, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Non-Receptor, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Protein Tyrosine Phosphatase, Non-Receptor Type 11

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