JoséMaríaRojo, Pilar Portolés
98
stimulatory molecules like CD28 and ICOS in T cells and CD19 in B cells also
possess Y-‐x-‐x-‐Mmotifs that can be phosphorylated to directly recruit PI3Kinases.
Cytokine receptors indirectly induce recruitment andactivationof class IAPI3Kby
means of different adaptor proteins. For instance, in IL-‐2 signaling IL-‐2 receptors
(IL-‐2R) recruits class IA PI3K upon phosphorylation of Tyr
338
of the
β
chain that
allows binding of the protein adaptors SHP2 andGab2, aswell as the Shc andGrb
adaptors that facilitate the formation of Grb-‐Gab2 o Grb-‐2-‐SHPS. On the other
hand, the PI3Kinase class IB p110
γ
catalytic subunits are activated by the
βγ
subunits of G-‐coupledprotein chemokine receptors having seven trans-‐membrane
peptide sequences. However, this separation among PI3K subclasses is not
absolute, asononehandclass IAp110
β
signaling throughG-‐coupledreceptorshas
been observed ((23), reviewed in (5)), and inT lymphocytes tyrosine kinases like
Lck and ZAP-‐70 can associate p110
γ
class IB subunits upon antigen receptor
activation (24). This is further complicated in lymphocytes, where p110
γ
mediate
PI3K-‐dependent chemokine signals inT lymphocytes, but p110
δ
performthe same
functions in B lymphocytes bymechanisms not well understood (25,26), but that
might involve tyrosinekinasesorRasmembersactivatedbyquimiokines (5).
Upon PI3K activation PtdIns(3,4,5)P
3
is generated that can be
dephosphorylated by the action of SHIP phosphatases to yield PtdIns(3,4)P
2
. Both
PtdIns(3,4,5)P
3
and PtdIns(3,4)P
2
recruit proteins with plectstrin homology (PH)
domains to cellmembranes, usually theplasmamembrane. Recruitedproteins can
then be activated to initiate signaling cascades. These proteins can vary, as PH
domains have certain selectivity concerning their interaction strengthwith these
phosphoinositides. In lymphocytes they include serine threonine kinases like the
phosphoinositide-‐dependent kinase 1 (PDK1) or Akt (PKB), Tec family tyrosine
kinases like Itk (inT lymphocytes) orBtk (inB lymphocytes), adaptorproteins like
GAB2, and small GTPase positive (Guanine nucleotide exchange factors (GEF) like
Vav)ornegative (GTPaseactivating factors (GAP)) regulatoryproteins.
4.a. TargetsofPI3K: PDK1, AktandmTOR.
Inmany cell types and in lymphocytes too, the serine threonine kinase Akt
plays a key mediator role in PI3K activated signals (3,18,27-‐29). Membrane-‐
recruitedAkt is activated upon phosphorylation in residue Thr
308
by PDK1 that is
also recruited through PH domains and activated by tyrosine kinases of the src-‐
family kinases like Lck (30). Akt P-‐Thr
308
then phosphorylates substrates like
Caspase 9, BAD or IKK
α
to prevent apoptosis, GSK3
β
to favour proliferation, and
the mTORC1 complex (the Rapamycin sensitive complex of mechanistic target of
Rapamycin (mTOR) containing Raptor) or its negative regulator TSC1/2 to favour
protein synthesis and cell growth. Akt is fully activated by phosphorylation of
Ser
423
by kinases generically termed PDK2. The main PDK2 is mTORC2, the
Rapamycin-‐insensitive complex of mTOR containing Rictor. mTORC2 activation is
