Kinase- Linked receptors

A single transmembrane helix links the outer receptor domain with the inner kinase domain. Ligand eg. Growth factor binding leads to dimerisation of pairs of receptors. The association of the 2 intracellular kinase domains allows an autophosphorylation of tyrosine residues to occur. The autophosphorylated tyrosine residues then serve as high affinity binding sites for other intracellular proteins, which form the next stage in the signal transduction cascade. One important group of such adapter proteins is known as the SH2 domain proteins.

The Ras/Raf pathway mediates the effect of many growth factors and mitogens. Ras functions like a G – protein and conveys the signal from the SH2 domain protein Grb, which is phosphorylated by the receptor tyrosine kinase. Activation of Ras in turn activates Raf, each of which phosphorylates and activates the next in line. The last of these MAP(mitogen activated protein) kinase, phosphorylates one or more transcription factors that initiate gene expression, resulting in a variety of cellular response, including cell division.

Jak stat Pathway

This pathway is involved in responses to many cytokines. Dimerisation of the receptors occurs when the cytokine binds and this attracts tyrosine kinase unit (Jak) to associate with and phosphorylate, the receptor dimer. Among the targets for phosphorylation by Jak are a family of transcription factors (Stats). These are the SH2 domain proteins that bind to the phosphortyrosine groups on the receptor – Jak complex and are themselves phosphorylated. Thus activated, stat migrates to the nucleus and activates gene expression.

References:

• Pharmacology by H.P.Rang, M.M.Dale and J.M.Ritter.

• Essentials of Medical Pharmacology by K.D.Tripathi