Class I phosphoinositide3-‐kinases in immunity…
99
also PI3K dependent and involves its association with ribosomes, yet the exact
mechanisms are not known (29). At least another well established PDK2 activity
for Ser
423
Akt phosphorylation is mediated by the DNA-‐PK (7,31,32). Doubly
phosphorylated Akt P-‐Thr
308
Ser
423
efficiently phosphorylates forkhead
transcription factor/forkheadbox (FOXO) transcription factorsFOXO1/2 to inhibit
their function,with important consequences in lymphocytes (27,33).
4.b. TargetsofPI3K:GEFsandTec.
The control by PI3Ks of the actin cytoskeleton dynamics mediated by GEF
stimulationof theRac andRhoGTPases iswell established (21).One typical GEF is
Vav, that isactivatedbySrcandSyk family tyrosinekinasesbut alsodependson its
PHandDbl-‐homologydomains foractivity(34).
With one exception, Tec family tyrosine kinases including BTK and Itk
expressed in B and T lymphocytes possess anN terminus PHdomain followed by
TH, SH3, SH2, and kinase domains (35,36). The PH domain is determinant to
recruitment of these Tec kinases to membranes, where they can further interact
with specific Tyr-‐phosphorylated substrates and activated by Src family and
autophosphorylation. Tec family tyrosine kinases have phospholipase C enzymes
like PLC
γ
as important substrates within signalosomes generated upon receptor
activation. PLC
γ
then splits PtdIns(4,5)P2 intoDiacylglicerol and Ins(1,4,5)P3 that
in turn are necessary to activate the Ser/Thr kinases PKC
θ
and hence the
Ras/MAPK and the IKK/NF
κ
B pathways, or the Ins(1,4,5)P3-‐Ca
2+
-‐dependent
activationofNFATfamilyof transcription factors (Figure3).
4.c. TargetsofPI3K: PDK1-‐dependent, Akt-‐independent.
PDK1 can associate to and activate additional substrates that are not
dependent on Akt including the Ser/Thr kinases PKC
θ
(37) and the cAMP-‐
dependent kinase PKA (38), with important functional consequences to
lymphocyteactivation.
Of note, although the different pathways initiated by PI3K activation have
specific targets, they canbealsoconnected to reinforceothers. For instance, PKC
θ
-‐
mediated activation of IKK/NF
κ
B is targeted in a PI3-‐dependent manner through
PDK1-‐,mTORC2-‐ andTec-‐dependentmechanisms.
5. CLASS I-‐PI3KINASES: RELEVANCETOCANCER
The clues for an association of PI3K and tumor development and growth
come from different sources. On one hand, some oncogenic retroviruses possess
genes derived from those encoding p110
α
and AKT. On the other, the
PtdIns(3,4,5)P3phosphatasePTENis a tumor suppressor gene frequentlymutated
in human tumors with the consequence of a constitutive activation of the PI3K
