Choice of STATs and Other Substrates Specified by Modular Tyrosine-Based Motifs in Cytokine Receptors
Abstract
Many members of the cytokine receptor superfamily initiate intracellular signaling by activating members of the Jak family of tyrosine kinases. Activation of the same Jaks by multiple cytokines raises the question of how these cytokines activate distinct intracellular signaling pathways. Selection of particular substrates—the transcriptional activator Stat3 and protein tyrosine phosphatase PTP1D—that characterize responses to the ciliary neurotrophic factor-interleukin-6 cytokine family depended not on which Jak was activated, but was instead determined by specific tyrosine-based motifs in the receptor components—gp130 and LIFR—shared by these cytokines. Further, these tyrosine-based motifs were modular, because addition of a Stat3-specifying motif to another cytokine receptor, that for erythropoietin, caused it to activate Stat3 in a ligand-dependent fashion.
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SHP2 is rapidly recruited to gp130 and phosphorylated by JAKs, which hints to a function as early feedback inhibitor.
“In response to IL-6 SHP2 is rapidly recruited to gp130 [8] and phosphorylated by JAKs [11], which hints to a function as early feedback inhibitor.”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [8]
SHP2 is crucial for IL-6-induced activation of the MAPK pathway.
“Beside it´s function as negative regulator of JAK/STAT signalling SHP2 is crucial for IL-6-induced activation of mitogen-activated protein kinase (MAPK) pathway [8, 14].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [8]
Phosphorylation of gp130 leads to dimerization of gp130 and activation of STAT1 and STAT3 as well as the SHP2-RAS-MAPK pathway.
“The phosphorylation of gp130 leads to dimerization of gp130 and activation of STAT1 and STAT3 as well as the SHP2-RAS-MAPK pathway (where SHP2 is Src homology 2 [SH2] domain-containing protein tyrosine phosphatase) (20-22).”
From The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury (2005) · cites this paper as [20]
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“Beside it ́s function as negative regulator of JAK/STAT signalling SHP2 is crucial for IL6-induced activation of mitogen-activated protein kinase (MAPK) pathway [8, 14].”
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- Authors
- Stahl, N., Farruggella, T. J., Boulton, T. G., Zhong, Z., Darnell, J. E., & Yancopoulos, G. D.
- Affiliations
- Regeneron (United States) (US)
- Rockefeller University (US)
- Laboratory of Molecular Cell Biology, Rockefeller University, New York, NY 10021, USA.
- ORCID
- Stahl, Neil
- Venue
- Science
- Published
- 1995-03-03
- Volume
- 267
- Issue
- 5202
- Pages
- 1349-1353
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2030624761
- Cited by
- 979
- References
- 1
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 9 · 2021: 8 · 2020: 11 · 2019: 14 · 2018: 11 · 2017: 20 · 2016: 22 · 2015: 18 · 2014: 18 · 2013: 23 · 2012: 24
- FWCI
- 49.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- cytokine receptors, JAK kinases, STAT3, tyrosine-based motif, gp130, LIFR, erythropoietin receptor, ligand-dependent signaling, transcriptional activation
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, DNA-Binding Proteins, Growth Inhibitors, Lymphokines, Membrane Glycoproteins, Molecular Sequence Data, Phosphorylation, Protein-Tyrosine Kinases, Recombinant Fusion Proteins, Tyrosine, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Protein Tyrosine Phosphatases, Point Mutation, Receptors, Cytokine, Intracellular Signaling Peptides and Proteins, STAT3 Transcription Factor, Cytokine Receptor gp130, Leukemia Inhibitory Factor, Receptors, OSM-LIF, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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