Biomedical Engineering Reference
In-Depth Information
subunit of PI3K protein), occurring in 32-37%, 10-17% and 15% of
cases, respectively, based on large population based studies [10-18].
7.2.1
RAS/RAF/MAPK Pathway
RAS is a 21 kDa GDP/GTP-binding protein (
G
uanosine
D
i
p
hosphate/
G
hosphate) that is localized at the inner surface of
the plasma membrane. RAS resides primarily in its inactive state
bound to GDP. RAS is triggered by upstream signals transmitted by
an activated EGFR, and stimulated to release GDP and exchange it
with GTP, via guanine nucleotide exchange factors (GEFs) [19]. RAS
activation is reversed by the GTPase activating proteins (GAPs) that
stimulate the GTPase activity of RAS leading to the hydrolysis of
bound GTP [20]. Phosphorylation of effector molecules leads to the
activation of downstream RAF and PI3K pathways.
uanosine
T
ri
p
is a well-known proto-oncogene mutated in several human
cancers including colorectal cancers. There are 3 RAS isoforms
encoded by the
RAS
genes. The vast majority of
mutations identified in colorectal cancers occur in the KRAS isoform,
the human homolog of the Kirsten rat sarcoma-2 virus oncogene
[17]. The most commonly affected amino acid residues are G12, G13,
and more rarely Q61 [17].
KRAS, NRAS
, and
HRAS
mutations are much less frequent
in colorectal cancer, accounting for less than 5% of mutations [21],
while
NRAS
mutations have not been identified [17]. The majority
of these mutations result in prolonged RAS activation by impairing
the GTPase domain of the RAS protein and conferring resistance
to the GAPs, ultimately leading to the constitutive activation of the
downstream growth promoting pathways [12].
Once activated RAS recruits the serine/threonine kinase
BRAF. Upon activation BRAF sequentially activates MEK (mitogen
activated ERK kinase) and ERK (extracellular signal-regulated
kinase) downstream effectors of the MAPK pathway. More than 30
different
HRAS
BRAF
mutations have been identified [17], but the
BRAF
V600E mutation constitutes about 90% of all activating
BRAF
mutations and is observed in 10-15% of colorectal tumors [22]. In
colonic cell lines harboring the V600E mutation, increased cellular
proliferation and inhibition of apoptosis is observed [23].
BRAF
and
activating mutations are often mutually exclusive events
suggesting only one mutation within the same pathway is sufficient
RAS
