Cells constantly send and receive signals to coordinate their activities through intricate signaling pathways. A protein known as Signal Transducer and Activator of Transcription 5, or STAT5, is a messenger in many of these pathways. For STAT5 to deliver its message, it must be activated through a process called phosphorylation, which acts as a molecular “on switch.” Phosphorylation is the addition of a phosphate group to the protein, a chemical modification that transforms STAT5 from an inactive to an active state.
The STAT5 Phosphorylation Pathway
The activation of STAT5 begins with an external signal, such as a cytokine or growth factor. These molecules, including prolactin and various interleukins, bind to specific receptor proteins on a target cell’s outer membrane. This binding changes the receptor’s shape, which activates enzymes on the inner side of the membrane called Janus kinases, or JAKs.
The primary job of these activated JAKs is to phosphorylate the STAT5 protein. There are two forms of the protein, STAT5A and STAT5B, which are encoded by separate but nearly identical genes. JAK enzymes add a phosphate group to a specific tyrosine amino acid on both STAT5A and STAT5B. This chemical addition is the step that switches STAT5 on, preparing it for its duties.
Cellular Functions Regulated by STAT5
Following phosphorylation, the added phosphate group causes two STAT5 proteins to pair up and form a structure known as a dimer. This STAT5 dimer then moves from the cell’s cytoplasm into the nucleus, which houses the cell’s genetic material. Once inside the nucleus, the STAT5 dimer regulates gene expression by binding to specific sequences of DNA. By attaching to these sites, the dimer acts as a transcription factor, a protein that controls which genes are turned “on” or “off,” leading to tangible biological outcomes.
The functions driven by STAT5 are diverse. For example, in response to the hormone prolactin, STAT5 activation is responsible for the development of mammary glands and the production of milk proteins. In the immune system, it is needed for the growth and function of T-cells, and it also plays a role in producing various blood cells (hematopoiesis).
Role in Disease Development
When STAT5 activation is dysregulated, it can lead to disease. Problems arise when the pathway becomes “constitutively” active, meaning it gets stuck in the “on” position without the proper external signals. This persistent activation causes STAT5 to continuously promote gene expression, which can have severe consequences.
Unchecked STAT5 activity is a feature in many cancers, especially blood cancers like chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). The constant signaling from phosphorylated STAT5 drives the uncontrolled proliferation and survival of malignant cells. In some leukemias, this hyperactivation indicates a more aggressive disease and is associated with poorer patient survival.
The role of dysregulated STAT5 is not limited to cancer. Imbalances in its signaling are implicated in certain autoimmune diseases, while insufficient activation can lead to immunodeficiency by impairing the development of immune cells.
Targeting STAT5 in Medicine
Because persistent STAT5 phosphorylation drives certain cancers, it is a focus for developing new medicines. The goal is to interrupt the overactive signaling pathway and halt cancer cell growth. A primary strategy is to target the enzymes that phosphorylate STAT5.
This approach led to a class of drugs known as JAK inhibitors. Medications like ruxolitinib work by blocking Janus kinase enzymes, which prevents STAT5 phosphorylation and shuts down the signal for cancer cells to proliferate.
While JAK inhibitors are effective, researchers are also exploring ways to target the STAT5 protein directly. Developing drugs to prevent its dimerization or ability to bind to DNA is chemically challenging but remains an active area of research for creating more specific therapies.