Receptor Tyrosine Kinase and MAPK Pathway
Receptor Tyrosine Kinase (RTK)
Types of catalytic receptors. i.e. receptor molecule also has catalytic activity.
Most RTKs are single-pass transmembrane proteins.
Have ligand-binding domain on the extracellular side.
Have tyrosine kinase domain on the intracellular side.
Example:
Receptors for insulin.
Receptors for growth factors e.g. EGF, PDGF.
Resting-State
Receptor molecules exist in monomeric form.
Activation and Signaling
Binding of the ligand
↓
Two receptor molecules come together and form a dimer
↓
Kinase domain of one receptor molecule phosphorylates tyrosine residues on the other receptor molecule
↓
Formation of phosphotyrosine (pY) motifs
↓
Binding of SH2 domain-containing protein. E.g:
• GRB2 ⟶ Leads to MAPK pathway
• PI3K ⟶ Leads to PI3K pathway
MAPK Pathway
Process from activation of receptor to the recruitment of GRB2 as explained above
↓
GRB2 attracts SOS (Son of Sevenless)
↓
SOS activates Ras
↓
Ras activates Raf-1 (MAP kinase kinase kinase)
↓
Raf-1 activates MEK (MAP kinase kinase)
↓
MEK activates MAPK (MAP kinase)
MAPK phosphorylates:
Proteins involved in cytoskeletal assembly and cell-matrix interaction ⟶ change in cell morphology and cell migration.
Transcription factors ⟶ Increase or decrease in transcription of genes involved in cell survival and proliferation.
PI3K Pathway
Process from activation of receptor to the recruitment of PI3K as explained above
↓
Phosphorylates PIP2 in the membrane
↓
Produces PIP3
↓
PIP3 serves as a binding site for many proteins e.g, PDK1 (3-phosphoinositide-dependent kinase 1), PKC, or guanine nucleotide exchange factor Vav
↓
Different protein has different downstream effect.
For example, PDK1 is seen downstream of insulin receptor
↓
Activates Akt (PKB)
↓
Akt inhibits glycogen synthase kinase 3-β