# Darnell, Kerr and Stark 1994: JAK-STAT pathways and transcriptional activation by interferons

Source: https://onco.cc/key-papers/paper-darnell-jak-stat-science-1994/  
OnCo record `paper-darnell-jak-stat-science-1994` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The review that defined the JAK-STAT pathway, the direct route by which interferons and many other cytokines tell a cell's genes to respond, and which is now the target of JAK inhibitors used in blood cancers.

## Summary

Darnell, Kerr and Stark drew together the genetics and biochemistry that revealed how interferons signal: receptor binding activates Janus kinases (JAKs), which phosphorylate STAT proteins that dimerise, move to the nucleus and switch on genes within minutes. They showed that the same JAK-STAT logic is shared by many cytokines and growth factors, each using a particular combination of JAKs and STATs. The paper gave the pathway its name and set out the model that has held since.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Science
- Year: 1994
- DOI: 10.1126/science.8197455
- Authors: Darnell JE Jr, Kerr IM, Stark GR.
- Findings: Interferon receptors activate JAK kinases, which phosphorylate STAT transcription factors that move directly to the nucleus.; Different cytokines use distinct combinations of the JAK and STAT family members.; The pathway provides a rapid, direct route from cell surface to gene activation.
- What it means: The JAK-STAT pathway explains how interferon and interleukin signals act in immunity and cancer. Its discovery underlies ruxolitinib and other JAK inhibitors in myeloproliferative neoplasms, the role of STAT3 in tumour-promoting inflammation, and the interferon-gamma signalling that determines whether tumours respond to checkpoint inhibitors.
- Caveats: A review from the pathway's early days; negative regulators such as SOCS proteins were described later.; Focused on interferons; oncogenic JAK2 mutations were discovered in 2005.

## Sources

- Full text (DOI): https://doi.org/10.1126/science.8197455

## Connected records

- key papers: [Grivennikov, Greten and Karin 2010: immunity, inflammation and cancer](https://onco.cc/key-papers/paper-grivennikov-immunity-inflammation-cancer-cell-2010/)
- targets: [Interferon alpha receptor (IFNAR1)](https://onco.cc/targets/ifnar1/), [JAK2](https://onco.cc/targets/jak2/)
- pathways: [JAK-STAT signalling](https://onco.cc/pathways/jak-stat/)
- terms: [Cytokine](https://onco.cc/terms/cytokine/), [Signalling pathway](https://onco.cc/terms/signalling-pathway/)

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