Kinase-Linked Receptors Overview

Kinase-Linked Receptors

• Kinase-linked receptors are a type of enzyme-linked cell surface receptor.
• They have two monomers.
• They have 7 transmembrane domains.
• Ligand binding triggers multiple cell responses.
• The energy molecule involved is ATP.
• Linked enzymes are enzyme kinases.
• Time scale is measured in hours.

Learning Outcomes

• Describe the structure of receptor tyrosine kinases.
• Explain the activation and signal transduction of receptor tyrosine kinases.
• Explain the insulin/insulin receptor signaling pathway and its role in metabolism.

GPCRs vs RTKs

• Definition: GPCRs are G protein-coupled receptors while RTKs are receptor tyrosine kinases.
• Structure: GPCRs have 7 transmembrane domains, RTKs have 2 monomers.
• Ligand Binding: GPCRs trigger only one cell response from a single ligand, RTKs trigger multiple cell responses from a single ligand.
• Energy Molecule: GPCRs use GTP, RTKs use ATP.
• Linked Enzymes: GPCRs do not have linked enzymes, RTKs use enzyme kinases.
• Time Scale: GPCRs response time is measured in seconds, RTKs response time is measured in hours.

Enzyme-Linked Receptors

• Discovered through growth factor investigation.
• Include nerve growth factor, platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor.
• Once activated, the enzyme acts like an enzyme or forms a complex with another enzyme.
• Can trigger multiple signal transduction pathways simultaneously.
• Involved in diseases like diabetes and cancer.

Structure of Receptor Tyrosine Kinases

• Consist of extracellular domains that bind ligands.
• Feature transmembrane domains.
• Intracellular domains with tyrosine kinase sites.
• Tyrosine kinase adds phosphate groups from ATP to tyrosine residues on target proteins.

Receptor Tyrosine Kinase Mechanism of Action (MOA)

• Many receptor tyrosine kinase variants have the same structure but different mechanisms of action.
• Phosphorylation leads to increased gene transcription.
• Main types include receptor tyrosine kinases, serine/threonine kinases, and cytokine receptors.
• Some cytokine receptors have no intrinsic kinase activity; they activate cytosolic tyrosine kinase.

Receptor Tyrosine Kinase Activation

• Ligand binding to RTK monomers results in dimer formation.
• The dimer's conformation changes, activating the kinase.
• One receptor phosphorylates a tyrosine residue within the "activation lip" of the other receptor.

Signal Transmission

• The activation lip moves out of the kinase active site, allowing ATP binding & kinase activity enhancement.
• Phosphorylation at conserved tyrosine residues creates "docking sites" for intracellular signaling proteins (e.g. SH2 domains).

Signal Transduction

• Signalling proteins (activated upon ligand binding) transmit signals into the cell's interior.
• Adaptor proteins facilitate signaling cascades.
• A message for cell proliferation occurs; gene mutations can make this pathway consistently "on" and cause cancer.
• Activated receptor tyrosine kinases are deactivated by being brought into the cell and digested by lysosomes.

Insulin Signaling (Simple Version)

• Insulin is produced and stored until needed.
• Released via other cell signaling pathways (endocrine signaling).
• Insulin binds to its receptor.
• Signal transduction results in glucose transporters relocating to the plasma membrane.
• Glucose uptake increases.

Insulin Signaling (Detailed)

• An overview of the insulin receptor signaling pathway demonstrates intricate pathways involving numerous proteins.
• Components such as glucose, SNARE complex, various kinases (PI3K, Akt, etc.), and transcription factors are key players.
• Pathways related to glucose transport, glycogen synthesis, and protein synthesis are highlighted.

Members of the Type II Receptor Tyrosine Kinase Family

• Includes insulin-like growth factor-1 receptor (IGF-1R).
• Components such as insulin receptor isoform A (InsR-A), insulin receptor isoform B (InsR-B), and other variants are part of this family.

Multiple Ligands and Receptors

• Multiple ligands can bind to different receptors, and some have preferential binding.
• An example provided is the IGF-II mitogen, related to cancer, and insR-A link to diabetes.
• Ligand binding activates receptors.

Regulation of Glucose Uptake

• Glucose transporters are stored in cytoplasmic vesicles.
• Insulin induces IRS-1/PI-3-kinase/PKB signaling.
• Vesicle translocation to the plasma membrane occurs.
• Vesicle fusion with the membrane allows glucose uptake into the cell.

Mitogen Effects

• Grb activates Ras, Raf, and the MAPK pathway.
• Phosphorylation activates transcription factors, which regulate gene expression.
• Some genes with insulin responsive elements are affected.

Summary of Receptor Tyrosine Kinases

• Generally, RTKs dimerize after ligand binding.
• This activates intrinsic cytoplasmic tyrosine kinases, leading to autophosphorylation of the cytoplasmic receptor domain.
• Adaptor proteins bind to the activated/phosphorylated receptor domain, activating other adaptor/signaling proteins.
• The signal propagates through the signaling cascade.

Insulin Example Summary

• Insulin binds to the already dimerized tetrameric insulin receptor.
• Ligand binding triggers autophosphorylation in the receptor's cytoplasmic domain.
• Insulin recruits IRS-1 for PI3-kinase/PKB signaling.
• The process causes glycogen uptake and synthesis.

Explore the fascinating world of kinase-linked receptors, focusing on their structure, activation, and the signaling pathways they influence. This quiz covers receptor tyrosine kinases, comparing them with G protein-coupled receptors (GPCRs) and delving into their critical roles in cellular responses and metabolism.