TAM receptors are a family of proteins found on cell surfaces, playing a role in cellular communication. The acronym TAM refers to three distinct but related proteins: Tyro3, Axl, and MerTK. As receptor tyrosine kinases, they transmit signals from outside the cell to its interior, influencing various cellular processes. Their presence across different cell types underscores their importance in maintaining the body’s internal balance.
How TAM Receptors Maintain Body Balance
TAM receptors contribute to body balance by clearing cellular debris and regulating immune responses. These receptors are activated by secreted ligands, primarily Growth Arrest-specific 6 (Gas6) and Protein S (Pros1), which undergo vitamin K-dependent modifications. These ligands act as bridges, connecting TAM receptors to other cells or particles and initiating intracellular signaling.
A primary function of TAM receptors is efferocytosis, the clearing of dead and dying cells. When cells undergo programmed cell death (apoptosis), they display “eat me” signals like phosphatidylserine. The Gla domain of TAM ligands allows for calcium-dependent binding to this phosphatidylserine, bridging the apoptotic cell to the TAM receptor on phagocytic cells, like macrophages. This interaction enhances the engulfment and removal of cellular remnants, preventing the release of harmful contents that could trigger inflammation.
Beyond cellular clearance, TAM receptors also regulate immune responses to prevent excessive inflammation. By facilitating the removal of apoptotic cells, they help to resolve inflammatory processes that might otherwise become chronic. Blocking TAM signaling can lead to widespread inflammation and an overactive immune system, potentially resulting in autoimmune conditions. This regulatory role helps maintain immune homeostasis.
When TAM Receptors Go Wrong
Dysregulation of TAM receptor activity can contribute to various disease states, disrupting the body’s normal balance. In cancer, TAM receptors, particularly Axl, are frequently overactive in many solid and liquid tumors, including lung, breast, ovarian, kidney, and pancreatic cancers, and leukemias. This heightened activity can promote tumor growth, facilitate metastasis, and help cancer cells evade detection and destruction by the immune system. Overactive Axl/Gas6 signaling can also lead to resistance to various cancer therapies.
Certain viruses exploit TAM receptors for their own benefit, a process known as apoptotic mimicry. Viruses such as Zika, Dengue, and Ebola utilize TAM receptors to gain entry into host cells, hijacking a natural cellular pathway. Some viruses can also use TAM receptor activation to suppress the host’s antiviral immune response, allowing the infection to persist and spread. This manipulation highlights how pathogens can subvert normal cellular functions.
Insufficient activity of TAM receptors can also contribute to chronic inflammation and autoimmune diseases. When efferocytosis is impaired due to reduced TAM function, dead cells and their contents accumulate, leading to persistent inflammatory signals. This inadequate clearance, coupled with a failure to properly suppress immune responses, can contribute to the development or exacerbation of autoimmune conditions. Elevated levels of Gas6, a TAM ligand, have been associated with inflammatory conditions like rheumatoid arthritis and systemic lupus erythematosus.
Targeting TAM Receptors for Treatment
Given their involvement in a range of diseases, TAM receptors are promising targets for new treatments. The ability to modulate their activity offers potential therapeutic avenues for conditions where these receptors are either overactive or underperforming. Researchers are exploring different strategies to either block or enhance TAM receptor signaling.
One approach involves developing inhibitors to block TAM receptor activity, particularly in cancers where their overactivity promotes disease progression. Small molecule tyrosine kinase inhibitors and inhibitory monoclonal antibodies are being investigated to prevent receptor dimerization and subsequent signaling. For instance, certain compounds aim to inhibit Axl or Gas6, which could disrupt tumor growth and improve responses to existing cancer therapies.
Alternatively, enhancing TAM receptor function is being explored for conditions characterized by insufficient activity, such as certain inflammatory or autoimmune diseases. By boosting efferocytosis or the dampening of immune responses, it may be possible to resolve chronic inflammation and restore immune balance. This dual potential, to either inhibit or activate, makes TAM receptors a versatile area of therapeutic research.