Targeting SOCS proteins to control JAK-STAT signalling in disease
Open accessAbstract
Defective regulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway in cancers, haematological diseases, and chronic inflammatory conditions highlights its clinical significance. While several biologic and small molecule therapeutics targeting this pathway have been developed, these have several limitations. Therefore, there is a need to identify new targets for intervention. Suppressor of cytokine signalling (SOCS) proteins are a family of inducible inhibitors of cytokine receptors that activate the JAK-STAT pathway. Here we propose that newly identified mechanisms controlling SOCS function could be exploited to develop molecularly targeted drugs with unique modes of action to inhibit JAK-STAT signalling in disease.
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Other approaches currently underway involve modulation of autoregulators of STAT3 activity, such as strategies to activate protein phosphatases, members of the protein inhibitors of activated STAT family, or SOCS protein members.
“Other approaches currently underway involve modulation of autoregulators of STAT3 activity, such as strategies to activate protein phosphatases, members of the protein inhibitors of activated STAT family, or suppressor of cytokine signaling (SOCS) protein members (Heppler and Frank, 2017; Durham et al., 2019).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Durham et al., 2019
The section “Exploiting SOCS interactions as new therapeutic targets” (pp. 11, 13) discusses strategies to enhance SOCS3 function and use SOCS3 mimetics to reduce STAT3 activation. The cited paper supports the SOCS approach, but the passages do not support the sentence’s separate approaches involving activation of protein phosphatases or protein inhibitors of activated STAT. (LLM, conf=0.87)
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Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases
Schwartz, D. M., Bonelli, M., Gadina, M., & O'Shea, J. J. (2016) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.167 · Cited by 648 · see citing works
The molecular basis of JAK/STAT inhibition by SOCS1
Liau, N. P. D., Laktyushin, A., Lucet, I. S., Murphy, J. M., Yao, S., Whitlock, E., Callaghan, K., Nicola, N. A., Kershaw, N. J., & Babon, J. J. (2018) · Nature Communications · doi:10.1038/s41467-018-04013-1 · Cited by 456 · see citing works
Kershaw, N. J., Murphy, J. M., Liau, N. P. D., Varghese, L. N., Laktyushin, A., Whitlock, E. L., Lucet, I. S., Nicola, N. A., & Babon, J. J. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2519 · Cited by 301 · see citing works
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Microglia polarization from M1 to M2 in neurodegenerative diseases
Guo, S., Wang, H., & Yin, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.815347 · Cited by 920 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
- Authors
- Durham, G. A., Williams, J. J. L., Nasim, M. T., & Palmer, T. M.
- Affiliations
- University of Bradford (GB)
- University of Glasgow (GB)
- University of Hull (GB)
- Corresponding author
- Palmer, Timothy M.
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 40
- Issue
- 5
- Pages
- 298-308
- ISSN
- 0165-6147 (ISSN-L)
- OpenAlex
- W2927217388
- Cited by
- 183
- References
- 3
- Citations by year
- 2026: 23 · 2025: 29 · 2024: 33 · 2023: 21 · 2022: 21 · 2021: 31 · 2020: 19 · 2019: 6
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- green
- eprints.gla.ac.uk
- Licence
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Funders
- British Heart Foundation (PG12/1/29276, PG14/32/30812)
- Great Britain Sasakawa Foundation (B70)
- Royal Society (43049)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- suppressor of cytokine signaling, JAK/STAT signaling, cytokine receptor signalling, targeted drug development, cancer, haematological diseases, chronic inflammation, small molecule drugs, biologic therapeutics
- MeSH terms
- Animals, Humans, Signal Transduction, STAT Transcription Factors, Suppressor of Cytokine Signaling Proteins, Janus Kinases, Small Molecule Libraries, Molecular Targeted Therapy
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