Receptor Tyrosine Kinase

All RTKs have an analogous molecular architecture with three domains:

1. The Extracellular Ligand-Binding Domain extends outside the cell and is responsible for binding to specific signaling molecules called ligands. Each RTK has its own set of ligands, and when a ligand binds to the receptor, it produces a conformational change in the receptor. These ligands can be growth factors, hormones, or other extracellular signaling molecules.
2. A Single Transmembrane α-helix spans the cell membrane, anchoring the receptor in place. It serves as a bridge between the extracellular and cytoplasmic domains.
3. An Intracellular Cytoplasmic Domain that has the tyrosine kinase activity. It adds phosphate groups (phosphorylate) to tyrosine residues on itself and other proteins, setting off a cascade of intracellular events. The kinase domain comprises several subdomains, including an ATP-binding site and a catalytic loop. When a ligand binds to the extracellular domain, it triggers a conformational change in the receptor, activating its kinase activity. This autophosphorylation event is a critical step in the RTK signaling cascade.

In addition to the above three domains, an RTK has additional carboxy (C-) terminal and juxtamembrane regulatory regions. The overall topology of RTKs is conserved from tiny nematode Caenorhabditis elegans to humans.

Again, some RTKs, like the Epidermal Growth Factor Receptor (EGFR), contain cysteine-rich domains in their extracellular regions. These domains are involved in stabilizing the receptor’s structure and ligand binding.

When signaling molecules bind to the ligand-binding domain of RTKs, they stimulate neighboring RTKs to attach, forming cross-linked dimers. This cross-linking brings the cytoplasmic tails of the receptors close to each other, activating the tyrosine kinase activity in these receptors. The activated tails phosphorylate each other on several tyrosine residues, a process known as autophosphorylation. Once phosphorylated, the tyrosines are the binding sites for signaling proteins that relay the message to another protein.

The signaling proteins bind to the phosphorylated tyrosines using a specific SH2 domain. Many such proteins bind to the cytosolic domain of an RTK, allowing the activation of different intracellular signaling pathways at the same time.

Some of the signaling pathways RTKs activate are MAPK/ERK pathway, PI3K/Akt pathway, and JAK-STAT pathway.

The mitogen-activated protein (MAP) kinase pathway is one of the most widely studied intracellular pathways triggered by RTKs.

MAPK pathway starts with the activation of Ras. It is a guanine nucleotide-binding protein associated with the cell membrane’s cytosolic face, similar to a G-protein. It is triggered by the signaling complexes related to receptor tyrosine kinases. In the inactive state, Ras is bound to GDP. When SH2-containing proteins bind to activated RTKs, they exchange GDP with GTP, thus activating the Ras protein.

Ras activation triggers a phosphorylation cascade of three protein kinases, members of the Mitogen-Activated Protein Kinases (MAP) kinases. The final enzyme of the cascade phosphorylates transcription regulators, leading to a change in gene transcription. Several growth factors, like nerve growth factor and platelet-derived growth factor, also utilize the RTK pathway for signaling. 

However, not all RTKs use the MAP kinase cascade to transcribe nuclear genes. For instance, insulin-like growth factor receptors use the phosphoinositide 3-kinase (PI3K) pathway, which phosphorylate inositol phospholipids in the cell membrane.

Some other RTKs utilize signal transducers and activators of transcription (STAT) proteins, which bind to the phosphorylated tyrosines in the cytosine and hormone receptors. An activated STAT moves into the nucleus and carries out transcriptional changes.

• RTKs are essential for the proper functioning of cells in eukaryotes.
• RTKs bind to diverse extracellular signaling molecules that help in cell-cell interactions and thus maintain tissue orientation and functioning of various organs in our body.
• RTKs determine gene transcription patterns by binding to signaling molecules like growth factors and hormones.
• Upon binding to RTKs, specific surface proteins called ephrins help in blood vessel maturation.
• The proper functioning of RTKs is essential for cell growth and differentiation and, thus, are targets of drugs used in cancer chemotherapy.