Receptor Tyrosine Kinases (RTKs) are a family of protein molecules found on the surface of cells that act as primary receptors for many extracellular signals, including polypeptide growth factors, certain hormones, and cytokines. These membrane-bound proteins function as molecular switches, receiving information from the outside environment and transmitting it deep inside the cell. RTKs initiate signal pathways that regulate fundamental cellular processes like division, survival, movement, and specialization.
Defining the RTK Structure
A Receptor Tyrosine Kinase is a single transmembrane protein characterized by three distinct sections. The extracellular domain extends outside the cell and is designed to specifically recognize and bind to a signaling molecule, known as a ligand. This binding domain varies across RTK families, allowing each receptor type to bind its unique signal.
The second section is a single alpha-helix that spans the cell membrane, anchoring the protein structure in place. This transmembrane domain is mostly hydrophobic and acts as a physical bridge between the exterior and interior of the cell. The final section is the cytoplasmic domain, which resides inside the cell and contains the intrinsic tyrosine kinase activity.
The RTK structure combines the receptor function (binding the signal) and the enzyme function (the tyrosine kinase) into one molecule. The kinase domain catalyzes the transfer of a phosphate group from adenosine triphosphate (ATP) to specific tyrosine residues on target proteins. This phosphorylation acts as the “on” switch for downstream signaling, linking the external signal to an internal cellular response.
The Signaling Cascade Mechanism
Activation begins when a specific ligand, such as an epidermal growth factor, binds to the extracellular domain. This binding causes a conformational change in the receptor structure, promoting the association of two individual receptor molecules to form a pair, a process called dimerization. Dimerization brings the two intracellular kinase domains close enough to interact.
Once paired, the kinase domain of one receptor phosphorylates multiple tyrosine residues on the cytoplasmic tail of its partner receptor. This process is known as trans-autophosphorylation, where the receptors activate each other. The phosphorylated tyrosine residues act as high-affinity docking sites for various intracellular signaling proteins.
These docking sites attract adaptor proteins containing specific binding domains, such as the SH2 domain. For example, the adaptor protein Grb2 binds to a phosphotyrosine on the receptor. Grb2 is associated with a guanine nucleotide exchange factor like SOS, which is recruited to the inner surface of the plasma membrane. This complex then activates the small G-protein RAS by promoting the exchange of GDP for GTP.
Activated RAS initiates the Mitogen-Activated Protein Kinase (MAPK) cascade. RAS activates the protein kinase RAF, which phosphorylates and activates MEK, which then activates ERK. ERK moves into the nucleus where it phosphorylates transcription factors, altering the expression of genes that control cell growth and division.
Roles in Normal Biological Function
RTK signaling is essential for the development and maintenance of organisms. They are the primary regulators of cell proliferation, ensuring that new cells are created only when and where they are needed, such as during growth or tissue turnover. RTKs also transmit anti-apoptotic, or cell survival, signals that prevent programmed cell death, maintaining tissue integrity.
RTKs also drive cell differentiation, the process where a less specialized cell becomes a more specialized one. Certain RTK signals are necessary for the proper development of muscle and nerve cells. In adults, RTKs are involved in tissue repair and regeneration, including wound healing and the formation of new blood vessels, known as neovascularization.
A prominent example of their metabolic function is the Insulin Receptor, a type of RTK that responds to the hormone insulin. Upon activation, this receptor initiates pathways that allow cells to take up glucose from the bloodstream, regulating overall blood sugar levels.
RTK Malfunction and Disease Pathways
When RTK signaling goes awry, it can contribute to the development of human diseases. The most significant pathology linked to RTK malfunction is cancer, where these receptors often become hyperactive. This dysregulation occurs through mechanisms like gene amplification, which leads to an excessive number of receptors, or through mutations that cause the receptor to be constitutively active, meaning it is permanently “on.”
An active RTK continuously sends growth signals down pathways like the RAS-MAPK cascade, leading to uncontrolled cell proliferation. This aberrant signaling contributes to cancer characteristics, including resistance to cell death, the ability to invade surrounding tissues (metastasis), and the promotion of new blood vessel growth (angiogenesis). Specific RTKs, such as the Epidermal Growth Factor Receptor (EGFR) and HER2, are frequently overexpressed or mutated in common cancers, including lung and breast malignancies.
Understanding these molecular defects has led to the development of targeted therapies known as Tyrosine Kinase Inhibitors (TKIs). Drugs like Lapatinib are designed to enter the cell and block the ATP binding pocket within the kinase domain, preventing the autophosphorylation step necessary for signal transmission. By specifically inhibiting the faulty RTK, these inhibitors can stop the uncontrolled growth signals.