Receptor Tyrosine Kinase and MAPK Pathway of Intracellular Signaling

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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

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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

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GRB2 attracts SOS (Son of Sevenless)

↓

SOS activates Ras

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Ras activates Raf-1 (MAP kinase kinase kinase)

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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

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Phosphorylates PIP2 in the membrane

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Produces PIP3

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PIP3 serves as a binding site for many proteins e.g, PDK1 (3-phosphoinositide-dependent kinase 1), PKC, or guanine nucleotide exchange factor Vav

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Different protein has different downstream effect.

For example, PDK1 is seen downstream of insulin receptor

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Activates Akt (PKB)

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Akt inhibits glycogen synthase kinase 3-β