Class I phosphoinositide3-‐kinases in immunity…
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PKC
θ
activated by diacylglicerol (DAG), or Serum-‐ and glucocorticoid-‐inducible kinase (SGK) 1.
PLC-‐
γ
is recruited to PI3P
3
containingmembranes to generate IP
3
and DAG; IP
3
induces enhanced
cytoplasmic Ca
2+
levels and activationof NF-‐AT transcription factors. DAGactivates not onlyNF-‐
κ
B
through PKC
θ
, but RasGRP that activates the Ras proteins, thus enhancing PI3K and other Ras-‐
dependent signals including theMAPKpathway.
One, then, faces a situationwhere class I PI3K, anenzyme essential tomany
cell functions is regulatedatmany levels, particularly: i)by theexpression levelsof
each regulatory and catalytic isoform of PI3K, of the different PtdIns(3,4,5)P
3
phosphatases, and the different activator and effector proteins of PI3K; and ii) by
thenatureof thesignals that activatePI3Kactivity indifferent cellsandconditions.
The final outcome of the cell response will depend on the integration of all these
factors. Furthermore, differences among different cells and tissues concerning
these factors allowfor distinct pharmacological effects of PI3Kinase inhibitors and
aselective intervention indifferentpathological situations.
As a general rule, the expression of class IA p110
α
and p110
β
is broad,
whereas class IA p110
δ
and class IB p110
γ
are mainly expressed by cells of
hematopoietic origin. Among class I PI3K, lymphocytes express readily detectable
amounts of class IA p110
δ
and class IB p110
γ
catalytic subunits that are
characteristic of leukocytes. Interestingly, in T lymphocytes class IA p110
α
is
expressed at levels similar to p110
δ
, but expression of p110
β
is low (14). The
particular function for the different class IA regulatory subunit isoforms is not
clearly established. Among class IA regulatory subunits, T lymphocytes express
lowamounts of p85
β
and p55
γ
chains ((14), and unpublished data), so p85
α
and
its splicing variants p55
α
and p50
α
are themain regulatory subunits (14). There
are clear variations in the abundance of these isoforms in resting and activated T
cells. Thus, resting CD4
+
T lymphocytes have similar levels of p85
α
and p50
α
, but
the levels of p50
α
is strongly reducedupon activation; low levels of p50
α
are also
common in T cell lines (14). In turn, p50
α
subunits bind better than p85
α
to
phosphorylated Tyr-‐x-‐x-‐Met motifs (14) and are preferentially recruited to
immunological synapses togetherwith ICOS (20). However, the functionalmeaning
of thesedifferences is far fromclear.
4. CLASS IAANDCLASS IBPI3KINASES:MAINMOLECULARMEDIATORS
In lymphocytes class I PI3Kinases are activated throughdifferent receptors
((21,22), Figure 3). The activity of Src and Syk tyrosine kinases is triggered by
ligand binding to antigen receptor complexes (BCR inB lymphocytes, TCR/CD3 in
T lymphocytes). This activation leads to phosphorylation of adaptor proteins like
LAT and TRIM in T cells or BCAP in B cells. Class IA PI3Kinases are typically
recruited tomembranes and activated upon phosphorylation of Y-‐x-‐x-‐Mmotifs in
theseproteins (i.e. inTRIM) or bymeans of adaptor proteins likeGrb-‐2or Cbl. Co-‐
