Non-receptor tyrosine kinases

 

Cytoplasmc Tyrsoine Kinases

 

About a third of the tyrosine kinase family are cytoplasmic tyrosine kinases. Many of these tyrosine kinases are linked to membrane receptors but unlike the receptor protein tyrosine kinases they are not covalently attached and the kinase domain is encoded by a separate gene.

The cytoplasmic kinases act in a similar way to the receptor tyrosine kinase in that they are responsible for phosphorylating the receptor and acting as docking sites for proteins to continue the signalling cascade.

 

 

SRC Kinase family

The largest family of cytoplasmic tyrosine kinases are the src family. They were first discovered in the Rous sarcoma virus and were found to cause cancer. It was later discovered that there was a cellular version of the src kinase and there have now been 9 mammalian members of the family discovered. The src tyrosine kinases consist of SH2 and SH3 domains and are located on the cytoplasmic side of the membrane. Each member is associated with different receptors and phosphorylate different target proteins.

viral src

 

 

Image courtesy https://en.wikipedia.org/wiki/File:PBB_Protein_SRC_image.jpg and has been released into the public domain.

 

Cytokine Receptors

 

An example of a group of membrane receptors that associate with tyrosine kinases are the cytokine receptors. These receptors are activated by cytokines which are extra cellular signals involved in cell-cell communication.

Interferons are cytokines that are released by white blood cells in response to viral infection. There role is to increase the resistance to viral infection of the cells not yet infected, by binding the receptors and inducing transcription of specific proteins.

Once activated by the interferon the receptor then triggers the jak-STAT signalling pathway. Jaks (Janus kinase) are the cytoplasmic tyrosine kinases that are closely associated with the receptors and are responsible for phosphorylating both the receptor and themselves. The receptors are composed of 2 or more polypeptide chains and are all associated with one of the four Jaks (Jak 1, Jak 2, Jak 3 and Tyk2). Signal Transducers and Activators of Transcription (STATS) which are proteins with SH2 domains then act downstream to relay the signal. This is a summary of the Jak-STAT pathway:

 

  1. Cytokine binds to the receptor.

  2. Receptors oligomerise.

  3. Jaks are activated and phosphorylate themselves and then the receptor.

  4. One of the seven STATS bind to the phosphotyrosine on each receptor via their SH2 domains.

  5. Jaks phosphorylate the STAT.

  6. The STAT dissociates from receptor and is released into cytoplasm.

  7. Two STATs come together to form either homo- or heterodimers.

  8. The dimerized STATs enter the nucleus.

  9. They bind to the DNA and activate gene transcription.

  10. A negative feedback mechanism in which genes for inhibitory proteins are also transcribed and they bind both the receptor and the STATs.

     

    Jak-STAT