Introduction to Receptor Tyrosine Kinases (RTKs)

• Definition: RTKs are a type of receptor that, upon binding to a ligand, undergo dimerization and autophosphorylation which activates their intrinsic tyrosine kinase activity.
• Course Objectives:
  • Understand RTKs and other kinase-linked receptors.
  • Describe RTK activation and its role in cell signaling and biological responses.
  • Relate RTKs to diseases like cancer and hypertension.

Overview of Receptor Types

• Four Main Types of Receptors:
  • Type 1: Ligand-gated ion channels
  • Location: Membrane
  • Effector: Ion channel
  • Examples: Nicotinic ACh receptors, GABAA receptor.
  • Type 2: G protein-coupled receptors (GPCRs)
  • Location: Membrane
  • Effector: Channel or enzyme, involves G proteins
  • Examples: Muscarinic acetylcholine receptors, adrenoceptors.
  • Type 3: Receptor kinases (RTKs)
  • Location: Membrane
  • Effector: Direct phosphorylation of proteins
  • Examples: Insulin, growth factor receptors.
  • Type 4: Nuclear receptors
  • Location: Intracellular
  • Effector: Gene transcription, involve DNA
  • Examples: Steroid receptors.

RTKs Characteristics

• Structure: RTKs are large proteins, consist of an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular tyrosine kinase domain.
• Functions: Mediate effects of growth factors, hormones (like insulin), and cytokines.
• Role in Biology: Involved in cellular processes such as division, differentiation, inflammation, and immune responses.

Activation Mechanism of RTKs

• Dimerization: Ligand binding induces dimerization of receptors, stabilizing their active conformation.
• Autophosphorylation: Dimerization activates the kinase domain, leading to the phosphorylation of tyrosine residues.
• Signaling Propagation: Phosphorylated tyrosines serve as docking sites for downstream signaling proteins (e.g., Grb2, Ras).

Examples of RTK Signaling

Epidermal Growth Factor Receptor (EGFR)

• Function: Stimulates cellular proliferation and plays a role in cancer development.
• Overview: Ligand binding results in receptor dimerization and subsequent autophosphorylation.

Insulin Receptor

• Function: Regulates glucose homeostasis.
• Structure: Composed of α and β subunits linked by disulfide bonds.
• Mechanism: Insulin binding induces conformational changes leading to receptor activation.

Signaling Pathways Activated by RTKs

• Ras-MAPK Pathway:
  • Activated by RTK-mediated autophosphorylation, leads to Grb2 binding and activation of Ras.
  • Ras activation triggers a kinase cascade involving Raf, MEK, and MAPK leading to transcriptional changes.
• PI3K Pathway:
  • RTK activation recruits PI3-kinase, converting PIP2 to PIP3, which activates PKB/Akt.
• Biological Effects: RTK signaling influences gene transcription, cell growth, survival, and migration.

RTKs in Disease

• Cancer: Overexpression or mutation of RTKs, such as HER2 in breast cancer, can lead to enhanced signaling and tumor growth.
• Hypertension: RTK signaling pathways, particularly involving VEGF, can contribute to vascular dysfunction and hypertension.

Therapeutic Implications

• Tyrosine Kinase Inhibitors (TKIs):
  • Used to treat various cancers, targeting overactive RTKs.
  • Examples: HERCEPTIN (targets HER2), Lapatinib (inhibits HER2 signaling).
• Management of TKI-Induced Hypertension: Utilization of angiotensin inhibitors and calcium channel blockers can effectively manage hypertension in patients undergoing TKI treatment.

Conclusion

• RTKs are critical regulators of various biological processes and play significant roles in diseases such as cancer and hypertension. Understanding their activation mechanisms and signaling pathways is vital for developing therapeutic strategies.