JoséMaríaRojo, Pilar Portolés
100
pathway. Another link is the observationof genomic amplificationof genes coding
for p110
α
(PIK3CA) or its target Akt (AKT) in several types of cancer (reviewed in
(39-‐41)). Although all Class I PI3K subunits have oncogenic potential
in vitro
; the
seminalworkby Samuels et al. (42), later confirmedby abundant data, shows that
thep110
α
catalytic isoformbut not other isoforms ismutatedwithhigh frequency
in colorectal and other different human cancer cells (39-‐41)). These gain-‐of
functionmutations of the
PIK3CA
gene are located in the ABD and C2 domains of
p110
α
, but particularly in thehelical andcatalyticdomains. Theenzymatic activity
is increased by different mechanisms including altered interaction between the
ABD and kinase domains of p110
α
, between the C2 domain and the p85 iSH2
domain, between the p85 nSH2 domain and the helical and kinase domains, or
between the kinase domain and the cell membrane, increasing accessibility to
phospholipidsubstrates.Mutations in the
PIK3R1
gene coding thep85
α
regulatory
subunit havebeenalsodescribed indifferent cancer cells. Theyareclustered in the
inter-‐SH2domainof p85 that contacts theC2domainof catalytic subunitsor in the
nSH2 domain that interacts with the helical domain of catalytic subunits; both
might interfere inhibitory interactions between subunits. Interestingly, these
cancer-‐derived gain-‐of-‐function mutations in p85
α
function through the p110
α
,
but not other PI3K catalytic subunits (43). Last, the p110
α
isoform of PI3K in
endothelium plays a role in tumor growth through its contribution to tumor
angiogenesis (44).
Gain-‐of-‐function E1021Kmutations of p110
δ
have been recently reported
in a residue of the catalytic domain similar to those found in p110
α
, but these
mutations are surprisingly associated with IgM hyperglobulinemia and
immunodeficiency rather than cancer (45). However, p110
δ
can favour tumor
growth by several documentedmechanisms. Firstly, in some human ovarian and
colorectal tumors
PIK3CD
transcripts can be alternatively spliced to generate a 37
kDa protein (p37δ) that maintains the ABD and RBD domains of p110
δ
. This
protein can enhance the proliferation and invasive properties of transformed cells
(46). In second place, p110
δ
activation can indirectly inhibit the activity of the
PTEN phosphatase by a mechanism involving RhoA (47). Enhanced p110
δ
expression in solid tumors in fact suppresses PTEN, contributing to cell growth
and –likely-‐ to cancer progression of malignancies of hematopoietic and non-‐
hematopoietic origin (48,49). The complexity of PI3Kinase activity regulation is
further highlighted by the ability of p85
α
to bind to and to activate PTEN in
transformedcell lines (reviewed in(50)).
