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.
Receptors for insulin.
Receptors for growth factors e.g. EGF, PDGF.
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
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)
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.
Process from activation of receptor to the recruitment of PI3K as explained above
Phosphorylates PIP2 in the membrane
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