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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

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

 

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