Friday, March 8, 2013

Signal Transduction Pathway - MAP Kinase Pathways (Part 1)

This pathway refers to the proteins that are highly conserved in evolution. The main role in this pathway is played by a family of serine/threonine kinases called the MAPK (mitogen activated protein kinases). Sometimes, ERK is also used as a synonym of MAPK. ERK stands for extracellular signal-regulated kinase). However, recently, ERK has been classified for a specific subset of mammalian MAPK.  ERK plays a critical and central role in cell proliferation. ERK is activated by growth factors binding to either protein tyrosine kinases or G-protein coupled receptors (GPCRs).
Lets see how this ERK/MAP kinases get activated? Here are two protein kinases upstream to that of ERK. These kinases are coupled to membrane receptors by Ras-GTP binding protein. When there is stimulation by growth factors, Ras which is a GTP binding protein gets activated. Ras when activated phosphorylates the Raf protein, a serine/threonine kinase. The Raf, then phosphorylates and activates the second protein called MEK (MAP kinases/ ERK kinase). MEK is an interesting protein that activates its downstream members of ERK family by phosphorylating at both threonine and tyrosine residues separated by 1 amino acid (for example, MEK phosphorylates threonine 183 and Tyrosine 185 of ERK2). When this ERK is activated, it phosphorylates a number of targets like protein kinases and transcription factors.
We have discussed Ras protein above as the central player of ERK pathway. Lets understand this protein a bit. We have heard about this protein as “oncogenic protein” i.e.; responsible for causing cancer. So, how it came to be known as oncogenic protein? Ras was first identified as the oncogenic protein of tumor virus that causes sarcoma in rats. The name Ras comes from ‘rat sarcoma virus’. Ras became as the protein of great interest in early 1980s when it was identified that the mutations in Ras can cause cancers in human. Various experiments were performed on normal mammalian cells. These experimental results with Ras showed that when active Ras protein is directly injected in normal mammalian cells, it induces proliferation. On the other hand, when the function of Ras protein is interfered by the injection of anti-Ras protein (antibody), the cell proliferation is blocked. Ras proteins are guanine nucleotide-binding protein. Remember the α-subunit of G-protein? Ras has the function which is analogous to that of the α-subunit of G-protein. Ras in inactive state is bound to GDP while in active state GDP gets exchanged with GTP. This activation of Ras is mediated by guanine-nucleotide exchange factors (GEFs) which helps in release of bound GDP and gets exchanged with GTP. However, there is one difference, Ras acts as a monomer rather than in association with βγ-subunits (as in case of G-protein). This is how the Ras gets activated. Now, it is necessary to terminate its activity when its function is over. So, here comes the role of GTPase-activating protein (GAPs). This GAP interacts with Ras-GTP resulting in hydrolysis of GTP thereby terminating the activity of Ras.

In the next post which will be the continuation of this post, we will see how Ras activation takes place downstream of protein tyrosine kinases; how the genes are induced by ERK and also the pathways of MAP kinase activation in mammalian cells.