Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase
Abstract
The haematopoietic protein tyrosine phosphatase (HePTP) is a negative regulator of the MAP kinases Erk1, Erk2 and p38. HePTP binds to these kinases through a kinase-interaction motif (KIM) in its non-catalytic amino terminus and inactivates them by dephosphorylating the critical phosphorylated tyrosine residue in their activation loop. Here we show that cyclic-AMP-dependent protein kinase (PKA) phosphorylates serine residue 23 in the KIM of HePTP in vitro and in intact cells. This modification reduces binding of MAP kinases to the KIM, an effect that is prevented by mutation of serine 23 to alanine. The PKA-mediated release of MAP kinase from HePTP is sufficient to activate the kinase and to induce transcription from the c-fos promoter. Expression of a HePTP serine-23-to-alanine mutant inhibits MAP-kinase dissociation and activation and induction of transcription from the c-fos promoter. We conclude that HePTP not only controls the activity of MAP kinases, but also mediates crosstalk between the cAMP system and the MAP-kinase cascade.
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cAMP and PKA signaling pathways interact with cytokine signaling pathways, including NF-κB, MAPK and Jak-STAT pathways.
“cAMP and PKA signaling pathways also interact with cytokine signaling pathways, including NF-κB, MAPK and Jak-STAT pathways.114–116”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [115]
While the KIM is required for binding, residues outside the KIM contribute to both binding and specificity.
“While the KIM is required for binding, 38,39 multiple reports have shown that residues outside the KIM contribute to both binding and specificity.40,41”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [39]
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References 48 · Cited by 203
- Authors
- Saxena, M., Williams, S., Taskén, K., & Mustelin, T.
- Affiliations
- Sidney Kimmel Cancer Center (US)
- University of Oslo (NO)
- Corresponding author
- Mustelin, Tomas
- Venue
- Nature Cell Biology
- Published
- 1999-08-11
- Volume
- 1
- Issue
- 5
- Pages
- 305-310
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1551845545
- Cited by
- 203
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 8 · 2012: 3
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r01ai041481-01)
- National Institute of Allergy and Infectious Diseases (R01AI035603, AI41481, AI40552, AI 35603)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- protein kinase A, mitogen-activated protein kinase, ERK1, ERK2, p38 MAPK, serine phosphorylation, protein dephosphorylation, MAPK activation, c-fos promoter, signaling crosstalk
- MeSH terms
- Alanine, Humans, Models, Chemical, Phosphorylation, Recombinant Proteins, Serine, Substrate Specificity, Signal Transduction, Mutagenesis, Site-Directed, Protein Tyrosine Phosphatases, Cyclic AMP-Dependent Protein Kinases, Jurkat Cells, Amino Acid Substitution, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Non-Receptor
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