Lecture 3: Receptor Tyrosine Kinases and Cancer

Module 8 Topic 3: Receptor Tyrosine Kinase, Cell Growth, and Cancer

Overview of Receptor Tyrosine Kinases (RTKs)

  • Definition: Receptor tyrosine kinases are a class of membrane receptor proteins crucial for various cellular processes.
  • Classification: RTKs are the second largest class of membrane receptors, following G protein-coupled receptors (GPCRs).
  • Focus: This discussion will center on the role of RTKs in cancer rather than their typical function in growth factors.

Key Concepts

Mutations and their Impacts
  • Mutations can lead to cancer in multiple ways:
    • Functional mutations can cause uncontrolled cell growth and proliferation without the necessary signaling cues.
    • Loss of expression of tumor suppressor proteins can remove regulatory mechanisms that prevent cancer development.
  • Example: The RAS protein plays a significant role in oncogenesis and is known to be mutated in various cancers.
Signaling Pathways
  • Two primary mutations:
    • Gain of function mutations in oncogenes (e.g., RAS).
    • Loss of function mutations in tumor suppressor genes.

Mechanism of Receptor Tyrosine Kinases

  • Cytoplasmic Domains: The cytoplasmic domain of RTKs functions as a kinase that uses ATP to phosphorylate specific proteins, including itself (autophosphorylation).
  • Key signaling proteins in RTK pathways:
    • MAP Kinase: Activated by RTK signaling.
    • GRAB2 (GRB2): An adapter protein crucial in signaling pathways.
    • AKT: Important in the insulin signaling pathway and related to glucose metabolism.
    • PI3 Kinase: Phosphorylates membrane lipids activated through insulin pathway signaling.
    • RAS: A small G protein crucial for intracellular signaling, activated through GDP-GTP exchange and possessing intrinsic GTPase activity.
Dimerization of Receptors
  • RTKs require dimerization for activation:
    • Mechanism: Upon ligand binding (like epidermal growth factor, EGF), two monomers come together to form a dimer—each receptor phosphorylates the other in their cytoplasmic tails.
    • Phosphotyrosines as Binding Sites: The phosphorylated tyrosines act as docking sites for other signaling proteins, propagating the signal within the cell.

Specific RTK Examples

Epidermal Growth Factor Receptor (EGFR)
  • Two-Step Activation Process:
    1. Binding of EGF induces dimerization of EGFR.
    2. Cross-phosphorylation of tyrosine residues occurs between the monomers.
  • Signaling Cascade: Leads to recruitment of proteins with SH2 domains (like GRAB2).

Adapter Proteins and Their Role

  • GRAB2 (GRB2) as a central player in signaling:
    • Structure: Contains SH2 domain for binding phosphotyrosines and multiple SH3 domains for recruiting downstream proteins like SOS.
    • Role: Functions as an adapter that links RTKs to other signaling pathways.
  • SOS (Son of Sevenless Protein): Functions as a GEF (guanine nucleotide exchange factor) that activates RAS protein by promoting GDP release and GTP binding.
RAS Protein Reactivation and Gain of Function Mutations
  • GAP Proteins: Involved in GTP hydrolysis; halt RAS signaling by converting it to an inactive GDP-bound state.
  • Mutant RAS: Common mutations occurring at glycine 12 in the RAS gene result in loss of GTPase activity, leading to continuous active signaling promoting cell proliferation, often seen in cancer (e.g., pancreatic cancer).
    • Somatic mutations: Most cancer-related mutations arise as somatic rather than inherited.

Oncogenic Mutations in RAS

  • Common Mutants:
    • Gly12Asp: Found in 36% of pancreatic cancers, resulting in weak GTP binding and decreased GAP binding.
    • Gly12Val: Found in 22% of cases, maintaining GTP binding but with diminished GAP interaction.
    • Other Less Common Mutations: Including those converting glycine to cysteine, serine, or alanine.
  • Clinical Implication: Approximately 22% of pancreatic cancer cases do not exhibit detectable mutations in RAS, indicating a complex nature of cancer development beyond single pathways.

Conclusion

  • Understanding receptor tyrosine kinases and their signaling mechanisms is essential in discerning their roles in growth regulation and cancer.
  • The interplay of mutations in these signaling pathways demonstrates a critical area for future therapeutic targeting.