The Abelson (Abl) kinase is a protein that relays signals within cells, directing a variety of processes. First identified as a gene involved in leukemia, it is also important for the normal operation of cells. Understanding Abl kinase provides insight into cell regulation and the development of targeted therapies for diseases like cancer.
What Are Kinases?
Kinases are enzymes with a widespread function inside cells. Their primary role is to transfer a phosphate group from adenosine triphosphate (ATP) to other proteins. This process is known as phosphorylation.
This change acts as a molecular switch, turning a protein’s function on or off, or fine-tuning its activity. Phosphorylation is a communication mechanism within the cell, controlling events like metabolism, cell growth, and division. The control exerted by kinases ensures that cellular activities are carried out at the right time and in the correct sequence.
The Abl Kinase Protein: A Closer Look
The Abl kinase, encoded by the ABL1 gene, is a nonreceptor tyrosine kinase, meaning it operates within the cell and phosphorylates tyrosine amino acids on its target proteins. Its structure is composed of several distinct regions called domains. These include the SH3, SH2, and kinase domains, which work together to control the protein’s function. The SH3 and SH2 domains are involved in recognizing and binding to other proteins.
Under normal conditions, Abl kinase activity is tightly controlled. The protein exists in a “closed” or inactive state where the SH3 domain binds to an internal linker region, and the SH2 domain interacts with the kinase domain itself. This forms a clamp that blocks its function. This autoinhibition ensures the kinase only becomes active when specific signals cause the protein to shift into an “open,” active state, where it participates in cell migration, division, and stress responses.
When Abl Kinase Goes Awry: The Link to Cancer
The connection between Abl kinase and cancer is clearly demonstrated in chronic myeloid leukemia (CML). In CML, a genetic event occurs where part of chromosome 9, containing the ABL1 gene, fuses with the BCR gene on chromosome 22. This creates a hybrid gene called BCR-ABL, and the resulting fused chromosome is known as the Philadelphia chromosome, a defining feature of CML.
The BCR-Abl fusion protein disrupts the regulated autoinhibitory structure of Abl. This results in a kinase that is permanently “switched on,” continuously sending signals that promote uncontrolled cell growth and division. This signaling drives the overproduction of white blood cells characteristic of leukemia. While this fusion is the classic example, dysregulated Abl kinase activity is also found in solid tumors, such as breast and lung cancer.
Therapeutic Approaches: Inhibiting Abl Kinase
The discovery of the BCR-Abl fusion protein’s role in CML led to the development of new cancer drugs. These therapies, known as tyrosine kinase inhibitors (TKIs), are designed to block the activity of the malfunctioning kinase. The first of these, imatinib, significantly changed the treatment of CML.
Imatinib works by fitting into the ATP-binding pocket of the Abl kinase domain. By occupying this site, the drug prevents ATP from binding, thereby blocking phosphorylation. This action turns off the “always on” signal from the BCR-Abl protein, halting the uncontrolled proliferation of cancer cells. For many patients, TKI treatment has transformed CML into a manageable chronic condition.
Overcoming Hurdles in Abl Kinase Treatment
While TKIs have been successful, drug resistance can arise during treatment. Resistance often occurs when new mutations develop in the BCR-Abl gene, which can alter the shape of the ATP-binding pocket where the inhibitor binds.
These changes can prevent the TKI from fitting effectively, allowing the kinase to resume its function. To counter this, second and third-generation TKIs have been developed. These newer drugs are designed to be effective against many common mutations, providing treatment options for patients whose cancer no longer responds to the initial therapy.