MERTK - MER proto-oncogene, tyrosine kinase | Elisa - Clia - Antibody - Protein

Background

MERTK (MER Proto-Oncogene, Tyrosine Kinase) is a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinase family, which plays a crucial role in the regulation of immune response, cell survival, migration, and phagocytosis. This gene was identified due to its homology with the avian oncogene v-Mer and is involved in the clearance of apoptotic cells and immune tolerance. The MERTK protein is primarily expressed in macrophages, dendritic cells, and retinal pigment epithelial cells. Dysregulation of MERTK has been implicated in various diseases, including cancer, autoimmune disorders, and retinal degenerative diseases.

Protein Structure

MERTK is a transmembrane protein with a complex structure that facilitates its function as a receptor tyrosine kinase:

1. Extracellular Domain: The extracellular region of MERTK consists of two immunoglobulin-like (Ig-like) domains followed by two fibronectin type III (FNIII) domains. These domains are essential for ligand binding. The primary ligands for MERTK are Gas6 (Growth arrest-specific 6) and Protein S, both of which bridge MERTK to phosphatidylserine on the surface of apoptotic cells.
2. Transmembrane Domain: This domain anchors the receptor in the cell membrane, enabling it to transmit extracellular signals into the cell.
3. Intracellular Tyrosine Kinase Domain: The intracellular portion contains the tyrosine kinase domain responsible for the phosphorylation of tyrosine residues. This kinase activity triggers downstream signaling pathways involved in cellular responses such as phagocytosis and anti-inflammatory processes.

Classification and Subtypes

MERTK belongs to the TAM receptor family, which also includes TYRO3 and AXL. This family is characterized by their similar structural domains and functional roles in immune regulation and cell clearance. Unlike other receptor tyrosine kinases, the TAM receptors are primarily involved in the clearance of apoptotic cells and regulation of immune responses rather than cell proliferation.

Function and Biological Significance

MERTK plays several critical roles in cellular processes:

1. Phagocytosis: MERTK is vital for the clearance of apoptotic cells by macrophages and dendritic cells. The binding of its ligands, Gas6 and Protein S, to phosphatidylserine on apoptotic cells activates MERTK, promoting the engulfment and digestion of these cells. This process prevents the release of potentially harmful cellular contents and maintains tissue homeostasis.
2. Immune Regulation: MERTK signaling suppresses inflammatory responses and promotes immune tolerance. By facilitating the clearance of apoptotic cells, MERTK prevents the release of inflammatory cytokines and promotes the production of anti-inflammatory mediators, thereby preventing autoimmunity.
3. Cell Survival and Migration: Activation of MERTK supports cell survival and migration through various downstream signaling pathways, including the PI3K/Akt and MAPK/ERK pathways. These pathways are essential for cell proliferation, differentiation, and movement.
4. Retinal Health: In the retina, MERTK is expressed in retinal pigment epithelial (RPE) cells, where it plays a crucial role in the phagocytosis of photoreceptor outer segments. This function is essential for the maintenance of photoreceptor health and visual function.

Clinical Issues

Alterations in MERTK expression or function have been associated with several diseases:

1. Cancer: Overexpression or aberrant activation of MERTK has been linked to various cancers, including leukemia, melanoma, and non-small cell lung cancer. MERTK contributes to tumorigenesis by promoting cell survival, proliferation, and migration. It also creates an immunosuppressive tumor microenvironment by inhibiting anti-tumor immune responses.
2. Autoimmune Diseases: Dysfunctional MERTK signaling can lead to impaired clearance of apoptotic cells, resulting in the accumulation of cell debris and triggering autoimmune responses. This mechanism has been implicated in systemic lupus erythematosus (SLE) and rheumatoid arthritis.
3. Retinal Degeneration: Mutations in the MERTK gene cause retinal degenerative diseases, such as retinitis pigmentosa. These mutations impair the ability of RPE cells to phagocytose photoreceptor outer segments, leading to photoreceptor cell death and progressive vision loss.

Summary

MERTK is a critical receptor tyrosine kinase involved in the regulation of immune response, cell survival, and phagocytosis. Its structure, featuring extracellular Ig-like and FNIII domains, a transmembrane region, and an intracellular tyrosine kinase domain, enables it to mediate these processes effectively. MERTK's role in clearing apoptotic cells, suppressing inflammation, and maintaining tissue homeostasis is vital for normal cellular function. Dysregulation of MERTK contributes to the pathogenesis of various diseases, including cancer, autoimmune disorders, and retinal degeneration. Understanding MERTK's functions and mechanisms provides valuable insights into potential therapeutic targets for these conditions.