The Story of JAK1

The gatekeeper of the cell.

The ancient Romans worshipped a two-faced god named Janus and it is after him the JAK genes are named. The ancient Romans worshipped a two-faced god named Janus and it is after him the JAK genes are named. His presence in religious ceremonies was ubiquitous; the ritual invocation of his name opened all holy celebrations. His two symbols, the key and the staff, represented his place as the protector of doorways and gates. His dual visage was a reminder that he presides over all beginnings and transitions, regardless of whether or not the change it blesses is sacred or profane. In times of peace, his temple doors would remain open; in times of war, they would be shut. Janus ruled the start and the conclusion of conflict, and all of the passageways in between. And it is for him, the god of doorways, for which the Janus kinases are named.

The JAK1 gene codes for one of these Janus kinases and, simply put, a JAK1 mutation can change the way the door to the cell is opened. When the door is left ajar, as it often is with the JAK1 mutations, cancer can find a foothold.

Initially, the JAK proteins were named for the acronym “just another kinase,” a testament to the
spectacularly dry naming conventions of molecular biology. In the mid-1990s, scientists discovered the role of these kinases in the JAK-STAT pathway, a crucial and widely-used method of cell signaling.

Much like teenagers the world over, cells need to talk to each other. Constantly. To meet this requirement, small signaling molecules called cytokines float through the blood, flipping biological on/off switches and delivering precise instructions. For example, the cytokine signaling molecule erythropoietin sends a message to the body to increase the production of red blood cells. This means that athletes who are comfortable in the grey area of performance-enhancing drugs can inject their bodies with an extra dose of this blood-boosting signal, resulting in more iron-rich, ketchup-y blood. More red blood cells in circulation means better oxygenation of the tissues. Blood doping is all about the cytokines: send a signal and let the body do the rest of the work.

There are many other kinases, of course: human growth hormone, prolactin (necessary for breastfeeding), and a variety of signaling proteins necessary for a functioning immune system. This is where JAK1 comes in.

The JAK1 pathway – which is to say, the series of events triggered by its activation – binds with signaling molecules first expressed by white blood cells (called interleukins) and signaling proteins that are released in response to pathogens (known as interferons). They also interact with a mouthful called “granulocyte-colony stimulating factor,” a protein that tells the bone marrow to make more of a certain family of white blood cell, named for the their grainy appearance. JAK1 opens the door for the
JAK-STAT pathways but is specifically involved in defending the body, immunity, blood production, growth, and neural development: deletion of this gene is lethal in mice (and presumably humans, as our JAK1 and their JAK1 genes are over 90 percent identical. Here’s how it works when everything is going to plan:

The JAK1 gene codes for the JAK1 protein. This protein makes its home
with its hand hanging out of the cell, so to speak, until it finds a buddy molecule that knows the secret shake. When the JAK1 protein comes upon a signaling molecule (cytokine), the ensuing biochemical handshake causes the shape of the protein to change, like the way, in a spooky movie, when someone touches the statue’s hand and the bookshelf turns into a door revealing a hidden passageway. The change in shape brings the important parts of the protein near to each other, which is where the biological magic happens. With the loops in tantalizing proximity to each other, the change allows the JAK1 proteins to activate each other. The activated proteins decorate some of the amino acids on the receptor; this step is called phosphorylation. The newly-phosphorylated tails on the receptor now undertake a recruitment mission of their own, flagging down other signaling substrates, notably the proteins of the STAT family. Once aboard, the STAT proteins join together and relocate to the nucleus of the cell, where they hang out with the DNA and regulate gene expression.

Plainly: JAK proteins are the ones who man the door at the club, deciding who gets in and when, as well as stamping hands to mark the partiers for entry. The proteins for which it holds the door open are part of a team that turns genes on and off. This is not a door one wants left open indefinitely. But a mutation in the JAK1 gene can result in a final protein product that not only opens the door to the JAK-STAT signaling pathway, but quite rudely leaves it open. Called constitutive mutations, these are known as activating, or gain-of-function mutations. Additionally, over-expression of JAK1 can promote cytokine independence, which means the cell becomes absolved of their requirement to follow orders.

JAK1 is also critical for interferon signaling, a cornerstone of the immune system. Inactivation of JAK1, then, can help cancer get a headstart by promoting the rouge cell’s evasion of anti-tumor immunological foot soldiers.

However, as far as cancer is concerned, the JAK1 “always on” gain-of-function mutations are perhaps the most relevant, implicated in T-cell acute lymphocytic leukemia (T-ALL), B-cell acute lymphocytic leukemia (B-ALL), acute myeloid leukemia (AML), ABC diffuse large B-cell lymphoma, and acute myeloid leukemia with severe congenital neutropenia. JAK1 mutations have also been found in hepatocellular carcinoma, breast cancer, and non-small cell lung cancer, among others. The JAK1 mutations implicated in T-ALL and B-ALL cancers are associated with advanced age and poor response to therapy.

Since the problems associated with JAK1 mutations often lies in how the important JAK-STAT pathway to
gene regulation is left open and active, therapies to counter its effects focus on closing or blocking the doorway. Recent developments in drug therapies for myeloproliferative neoplasms mean that clinicians can focus on easing the burden of these mutations and improving quality of life. Inhibitors of the JAK-STAT pathway have antiproliferative and anti-inflammatory effects; these drugs, like ruxolitinib, are approved not as a cure, but as a drug that can ease the symptoms and suffering of those affects. There is still much to learn about the Janus kinases and their relationship to various cancers, but the importance of this tiny doorman truly cannot be overstated. With time, it is our hope that we can learn to retrain the wayward gods of beginnings, openings, and safe passage.

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