Like all cell surface receptors, they also receive and transmit environmental signals. Epidermal growth factor receptors (EGFRs), insulin receptors (IRs), and platelet-derived growth factor receptors (PDGFRs) are some examples of RTKs. RTKs are essential in cellular growth, survival, differentiation, metabolism, and migration.
Structure of Receptor Tyrosine Kinases
How Receptor Tyrosine Kinase Works
Signaling Pathways Activated by RTKs
What Receptor Tyrosine Kinases Do in a Cell
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. 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. 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.
