An. Real. Acad. Farm. vol 80 nº 1 2014 - page 94

JoséMaríaRojo, Pilar Portolés
94
PI3Kinase inhibitors are specific formore thanone isoform, or that PI3K inhibitors
primarily aimed at inhibiting class I PI3Kinases significantly inhibit PIKK like
mTORorDNA-­‐PK(9).
3. CLASS IA AND CLASS IB PI3KINASES: STRUCTURE AND ACTIVATION,
CONTROLBYPHOSPHATASES
Class I PI3Kinases areheterodimers formedbyone catalytic of 110kDaand
one regulatory subunit of variable size (Figure 2). According to the nature of the
regulatory subunit theybind to, and themode they are classically activated, class I
PI3Kinases are further divided into class IA (Figure 2AandB) and class IB (Figure
2C). The former (catalytic subunits p110
α
, p110
β
, and p110
δ
) bind to any of five
regulatory subunit isoforms (p85
α
, p55
α
, p50
α
, p85
β
, and p55
γ
) all possessing
two SH2 domains separated by an alpha-­‐helix inter-­‐SH2 domain (iSH2) that
interacts with catalytic subunits; Class IA catalytic subunits are characteristically
activated through tyrosine kinase-­‐dependentmechanisms. Phosphorylation of the
Tyr residuesof Tyr-­‐x-­‐x-­‐Met is the initial step inducingbindingof SH2domains that
are conserved in all class IA regulatory isoforms. The p85, but not the p50 or p55
regulatory isoforms have additional SH3, proline rich and BCR-­‐homology GTPase
activation domain (BH-­‐domain) that might mediate binding
to small G proteins of
theRho/Rac/cdc42 family.
On the other hand, class IB catalytic subunit p110
γ
binds to regulatory
subunits p101 and p87 (Figure 2C). Subunit p101 is the main subunit in most
tissues; p101 and p85 differentially help in G protein–coupled receptor (GPCR)-­‐
induced PI3K activation, such that interaction of p101 with the Gβγ chains is
strong and efficient in recruitment of p110γ tomembraneswhereas p87 interacts
weakly with Gβγ chains and recruitment of p110γ needs additional interactions
withRas-­‐GTP(10).
Class I catalytic subunits are structured in domains with distinct function
(Figure 2A-­‐C); these include a N-­‐terminal adaptor binding domain (ABD) that
constitutively bind regulatory subunits, a Ras-­‐binding domain, the C2 and helical
domains that regulate theassociationwithregulatorysubunits, andoneC-­‐terminal
kinase domain. Interactions of class IA p110
α
and the iSH2 and amino-­‐terminal
domainof regulatoryp85
α
subunitshavebeendetermined indetail (11,12). In the
steady state, the p110-­‐p85 heterodimers have low enzymatic activity; however,
binding of SH2 domains to phosphorylated peptides disrupt the inhibitory
interactions including the one between the p85 nSH2 domain and the helical
domainof p110
α
(12,13). Given the inhibitorynatureof the regulatory subunits, it
should be noted that there are clear differences among catalytic isoforms
concerning their interaction strengthwith regulatory subunits (14). Inaddition, at
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