Physiology  Topics   

Receptor Tyrosine Kinases

In a receptor tyrosine kinase mechanism, two ligand-bound receptors dimerize and the tyrosine kinase domains phosphorylate a tyrosine residue on the cytosolic side of the other receptor (cross phosphorylation).

Phosphorylated receptor tyrosine kinase binds an adapter protein called GRB2. While the SF2 domain of GRB2 binds to phosphotyrosine, its SH3 domain binds a proline-rich region of Sos, a GTP-GDP exchange factor for Ras (a single-unit G-protein). Therefor, when the receptor is phosphorylated, it forms a complex with GRB2, Sos and Ras that activates Ras.

The protein kinase Raf binds to Ras, which brings Raf close to the inner face of the plasma membrane. There, Raf gets activated by membrane properties and/or lipids, and is now able to phosphorylate and activate another protein kinase, MEK. MEK phosphorylates and activates yet another protein kinase, MAP kinase.

MAP Kinase translocates to the nucleus where it phosphorylates and activates the transcription factor TCF. MAP kinase also phosphorylates and activates the transcription factor SRF. TCF and SRF activate the transcription of target genes containing a serum response element (SER).