Biology Reference
In-Depth Information
21
Is MKK a Metastasis Suppressor?
The MAPK Signalling Pathway
The Ras/Raf/MAPK signalling pathway is activated by many external stimuli, such
as growth factors, mitogens, inflammatory cytokines, apoptosis inducing factors and
others. Ras functions through its effector isoforms of Raf, namely Raf1 (C-Raf),
A-Raf and B-Raf, to activate the signalling cascade. Ligand binding activates Ras/
Raf1 which stimulates the signalling cascade involving MAP3K→MAP2K→MAPK
transducing the signal down the cascade leading to cellular responses like regula-
tion of transcription, cell proliferation, apoptosis, differentiation, development and
angiogenesis. The MAP3K, of which there are around 20 in number, seems to inte-
grate the signals transduced by the stimuli. Seven MAP2K have been identified.
MAP3K→MAP2K regulate five MAPK families generating a diversity of sub-routes
of flow of information towards achieving a wide range of phenotypic function.
External stimuli can differentially engage MAPK signalling. Thus growth factor
mediated activation of RTKs, and hormonal and neurotransmitter signals imparted
by GPCRs, for instance, activate Raf1 to engage MKK1 (MAP2K1/MEK1)→ERK1/
ERK2 (MAPK3/MAPK1) route to lead to cell survival, proliferation and differen-
tiation. Raf1 can stimulate signalling by another route by activating kinases such as
ASK1 (MAP3K, apoptosis signal regulating kinase 1) and STK3 (the serine threo-
nine kinase 3, MST2). This occurs independently of the kinase activity but by direct
binding to ASK1. Stress factors in the form of ROS (reactive oxygen species),
inflammatory cytokines, UV irradiation, deprivation of growth factors, etc. activate
the ASK1 route via MKK4/7 (MAP2K4/MEK4; MAP2K7/MEK7)→JNK1-3 (stress-
activated protein kinases SAPK1/MAPK8-10) or the MKK3/6 (MAP2K3/MEK3;
MAP2K6/MEK6)→ p38MAPK (MAPK14) to inflammation and apoptotic outcome
(Cuevas et al., 2007; Matallanas et al., 2011).
In essence the outcome of differential signalling might significantly impinge upon
the phenotype. Thus, mutations of Ras and Raf, which are encountered frequently
in cancers, deregulate extracellular signals stimulating cell proliferation and growth,
whilst the p38MAPK/JNK route leads to opposite effects of apoptosis and suppres-
sion of the neoplastic process.
MKK in Tumour Biology
The MAPK signalling cascade leads to cellular responses like regulation of tran-
scription, proliferation, apoptosis, differentiation and development in response to
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