MAP Kinase Kinase Kinase
MAP (Mitogen-activating protein) Kinase Kinase Kinase (also called MAP3K or MEKK, not MEK) is a type of protein kinase that phosphorylates other proteins, which include protein kinases such as Map Kinase Kinase (MEK). There is a family consisting of different types of MAP3Ks and they all react and respond to signals differently. It aids in intracellular control and helps determine the cells responses; cell proliferation, cell death, hormonal responses and cell differentiation. It acts as a messenger in the transduction pathway in order to deliver a message to the cell therefore, this particular protein kinase can generate many different responses in the cell.
The function of MAP3K is that it phosphorylates the Serine or the Threonine residues of MEK. This can be shown in the RAS signalling pathway. RAS is a monomeric G -Protein that can be is associated with SOS (Son of Sevenless) and is activated by enzyme-coupled receptors in the plasma membrane. The RAS G protein is activated by external signals such as epidermal growth factors (EGF) and radiation. The activated RAS binds to MAP3K in order to activate it and as a result, it is able to phosphorylate MEK, which is the next transducing protein kinase in the signalling pathway. In this signalling process, the MAP3K is called RAF and without it, the cascade of protein kinase would not occur and target DNA is not expressed.
The RAS signalling pathway:
- Signal molecule binds to tyrosine kinase receptor (enzyme-coupled).
- The two single monomers of receptor dimerise and autophosphorylate.
- Intracellular signal molecule, Grb-2 is bound to phosphorylated tyrosines and an Ras-GEF (SOS) protein attaches to the Grb-2.
- SOS activates RAS by causing it to take up GTP and release GDP.
- The activated RAS G- protein activates MAP Kinase Kinase Kinase (RAF) by binding to it.
- RAF phosphorylates MAP Kinase Kinase (MEK) and activates it. Hydrolysis of ATP also occurs at this point.
- MEK phosphorylates MAP Kinase (ERK) and activates it. Hydrolysis of ATP also occurs at this point.
- ERK then phosphorylates a variety of downstream proteins and either activate them or inactivates them.
- ↑ American chemical society (2001) MAP Kinases report. Available at: http://www.audreyli.com/panli/chemistry/reference/review/cr000241p.pdf (last accessed 23.11.2012)
- ↑ The company of Biologists (2005) Journal of cell science 118. Available at: http://jcs.biologists.org/content/118/16/3569.full.pdf (last accessed 23.11.2012)
- ↑ Berg.J, Stryer. L, Tymoczko. J; (2012)Biochemistry seventh edition, New York: W.H Freeman, Palgrave Macmillan, International Edition
- ↑ Alberts.B, Johnson.A, Lewis.J, Raff.M, Roberts.K, Walter.P (2008) Molecular Biology of the Cell Fifth Edition, New York: Garland Science, Taylor and Francis Group