Scientists peel away the mystery of JAK enzymes, which play roles in everything from eczema to ulcerative colitis

Pharmaceutical ads are difficult to avoid in American television programming and a growing number of them promote a class of medications called JAK inhibitors, using an acronym that assumes the average TV watcher knows exactly what JAK stands for.

With just a bit more information and attention to detail, the commercials could introduce viewing audiences to the complex family of JAK—pronounced jack—enzymes. They’re intimately involved in inflammation, which explains why this potent family is frequently a target of inhibitory medications. These drugs treat numerous conditions that range from ulcerative colitis to eczema to arthritis.

Now, scientists in Israel and Germany have taken a deep dive into the molecular biology of each member of the JAK family and found that they compete with each other when attempting to bind to cells. The discovery may eventually lead to the development of a new generation of therapeutics with mechanisms of action that differ from the current stable of inhibitors. The global team of collaborators sees the potential new group of medications as interventions for autoimmune disorders and various forms of immunodeficiency.

JAK stands for Janus kinases of which there are four—JAK1, JAK2, JAK3 and TYK2. The latter is known as tyrosine kinase, which isn’t the orphan of the family despite the name difference. All JAK kinases are tyrosine kinases and all are also Janus kinases. The name is derived from Janus the two-faced god of Roman mythology who could see in two different directions at once. One face of Janus looked to the future; the other had a sharp eye on the past.

Similarly, all members of the JAK enzyme family are known for their dual functionality. Each of the four possesses two phosphate-transferring domains—all JAKS attach phosphate compounds to the tyrosine tails of cytokines.

But just as the two faces of Janus the god were different, so too are the two domains of JAK family enzymes. One is in the active phosphate-transferring domain—that is, it’s the one that can attach a phosphate compound to the tyrosine tail of a cytokine. The other domain is purely regulatory, capable of mediating the enzymatic activity of the opposite domain.

“Janus kinases bind to class I and II cytokine receptors, activating signaling and regulating gene transcription,” writes Dr. Eyal Zoler, lead author of the new research on JAK family enzymes. The study is published in the journal Science Signaling.

Cytokines are tiny proteins that are secreted by cells, especially immune cells, and play a role in immune responses. Interferons, which play a role in the immune system’s response to viral and bacterial infections, are cytokines. Interferons also kill cancer cells and stop them from growing.

The take-home lesson about cytokines is that they serve as signaling molecules, which transmit chemical messages between cells and within cells. They need members of the JAK family to perform this vital job.

Signaling is the equivalent of a vast telecommunications network—albeit on a molecular level. Messages can affect which genes are activated in the nucleus. Zoler and colleagues found that when type I interferons proliferate at the surface of a target cell, the activity results in the recruitment of JAKs—JAK1 and TYK2 and the initiation of the signaling cascade. But it’s also possible that other members of the JAK family of enzymes will show up as well, Zoler and the team of researchers found.

“The signaling cascades of type I interferons are initiated by their binding to interferon-alpha1 and interferon-alpha-2,” added Zoler, a researcher at the Weizmann Institute of Science in Rehovot, Israel. “Our results indicate that interferon-alpha-1 and interferon-alpha-2 can recruit different JAK members with unexpected promiscuity; however, optimal signaling activity requires JAK1 and TYK2.”

Zoler and colleagues have demonstrated that receptor-binding competition among members of the Janus kinase family may explain why cytokine signaling can differ across various types of cells, a key finding in the current study. It is this discovery that helps explain how new classes of medications may grow from the team’s research.

Molecular biologists at Weizmann and their collaborators from the Center for Cellular Nanoanalytics at Osnabrück University in Germany describe Janus kinases as master molecules in the signaling cascade. While many intracellular signaling pathways lead from the cell surface to the nucleus, the one known as the JAK-STAT pathway, analyzed in the new study, is one of the most direct routes.

The team was able to develop a new understanding of JAK family enzymes by conducting a series of experiments with synthetic interferons and cell lines deficient in different members of the JAK family. They found that the interferon-alpha receptors were not restricted to activation by just TYK2 and JAK1 as prevailing scientific wisdom suggests. Multiple JAKs were able to bind competitively to interferon-alpha receptors to mediate signaling, depending on their relative abundances within the cell, the team revealed.

“Elucidating the molecular grammar underlying differential JAK usage, promises to uncover new therapeutic strategies for immunomodulation,” Zoler and his team concluded.

© 2025 Science X Network

Pharmaceutical ads are difficult to avoid in American television programming and a growing number of them promote a class of medications called JAK inhibitors, using an acronym that assumes the average TV watcher knows exactly what JAK stands for.

With just a bit more information and attention to detail, the commercials could introduce viewing audiences to the complex family of JAK—pronounced jack—enzymes. They’re intimately involved in inflammation, which explains why this potent family is frequently a target of inhibitory medications. These drugs treat numerous conditions that range from ulcerative colitis to eczema to arthritis.

Now, scientists in Israel and Germany have taken a deep dive into the molecular biology of each member of the JAK family and found that they compete with each other when attempting to bind to cells. The discovery may eventually lead to the development of a new generation of therapeutics with mechanisms of action that differ from the current stable of inhibitors. The global team of collaborators sees the potential new group of medications as interventions for autoimmune disorders and various forms of immunodeficiency.

JAK stands for Janus kinases of which there are four—JAK1, JAK2, JAK3 and TYK2. The latter is known as tyrosine kinase, which isn’t the orphan of the family despite the name difference. All JAK kinases are tyrosine kinases and all are also Janus kinases. The name is derived from Janus the two-faced god of Roman mythology who could see in two different directions at once. One face of Janus looked to the future; the other had a sharp eye on the past.

Similarly, all members of the JAK enzyme family are known for their dual functionality. Each of the four possesses two phosphate-transferring domains—all JAKS attach phosphate compounds to the tyrosine tails of cytokines.

But just as the two faces of Janus the god were different, so too are the two domains of JAK family enzymes. One is in the active phosphate-transferring domain—that is, it’s the one that can attach a phosphate compound to the tyrosine tail of a cytokine. The other domain is purely regulatory, capable of mediating the enzymatic activity of the opposite domain.

“Janus kinases bind to class I and II cytokine receptors, activating signaling and regulating gene transcription,” writes Dr. Eyal Zoler, lead author of the new research on JAK family enzymes. The study is published in the journal Science Signaling.

Cytokines are tiny proteins that are secreted by cells, especially immune cells, and play a role in immune responses. Interferons, which play a role in the immune system’s response to viral and bacterial infections, are cytokines. Interferons also kill cancer cells and stop them from growing.

The take-home lesson about cytokines is that they serve as signaling molecules, which transmit chemical messages between cells and within cells. They need members of the JAK family to perform this vital job.

Signaling is the equivalent of a vast telecommunications network—albeit on a molecular level. Messages can affect which genes are activated in the nucleus. Zoler and colleagues found that when type I interferons proliferate at the surface of a target cell, the activity results in the recruitment of JAKs—JAK1 and TYK2 and the initiation of the signaling cascade. But it’s also possible that other members of the JAK family of enzymes will show up as well, Zoler and the team of researchers found.

“The signaling cascades of type I interferons are initiated by their binding to interferon-alpha1 and interferon-alpha-2,” added Zoler, a researcher at the Weizmann Institute of Science in Rehovot, Israel. “Our results indicate that interferon-alpha-1 and interferon-alpha-2 can recruit different JAK members with unexpected promiscuity; however, optimal signaling activity requires JAK1 and TYK2.”

Zoler and colleagues have demonstrated that receptor-binding competition among members of the Janus kinase family may explain why cytokine signaling can differ across various types of cells, a key finding in the current study. It is this discovery that helps explain how new classes of medications may grow from the team’s research.

Molecular biologists at Weizmann and their collaborators from the Center for Cellular Nanoanalytics at Osnabrück University in Germany describe Janus kinases as master molecules in the signaling cascade. While many intracellular signaling pathways lead from the cell surface to the nucleus, the one known as the JAK-STAT pathway, analyzed in the new study, is one of the most direct routes.

The team was able to develop a new understanding of JAK family enzymes by conducting a series of experiments with synthetic interferons and cell lines deficient in different members of the JAK family. They found that the interferon-alpha receptors were not restricted to activation by just TYK2 and JAK1 as prevailing scientific wisdom suggests. Multiple JAKs were able to bind competitively to interferon-alpha receptors to mediate signaling, depending on their relative abundances within the cell, the team revealed.

“Elucidating the molecular grammar underlying differential JAK usage, promises to uncover new therapeutic strategies for immunomodulation,” Zoler and his team concluded.

© 2025 Science X Network