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the PDE4D/
b
-arrestin complex upon TCR/CD28 costimulation (Bjorgo et al.
2010
). Interestingly, PKB was shown to be recruited to lipid rafts concurrently
with
b
-arrestin in TCR/CD28 costimulated T cells. In addition, we found that PKB
coimmunoprecipitated with
b
-arrestin in TCR/CD28 costimulated T cells, and it
was further demonstrated that PKB,
b
-arrestin, and PDE4 through defined contact
areas indeed form a trimolecular interaction where
b
-arrestin interacts directly with
both PKB and PDE4 (Bjorgo et al.
2010
).
Binding of the PKB PH domain to PIP3 recruits PKB from the cytosol and is also
thought to induce a conformational change that converts PKB into a substrate that
can be activated by the associated phosphoinositide-dependent kinase 1 (PDK1)
(Milburn et al.
2003
). Lately, several reports have demonstrated that
b
-arrestin can
function as a signaling scaffold by assembling either positive or negative regulators
of the PKB pathway. More specifically,
b
-arrestin 2 has been reported to be
involved in PKB signaling downstream of the dopamine receptor in neurons
where dopamine stimulates formation of a signaling complex consisting of
b
-arrestin 2, PKB, and protein phosphatase 2A (PP2A) (Beaulieu et al.
2005
).
Furthermore, the PI3K-PKB pathway has been reported to be activated in a
b
-arrestin 1-dependent manner upon stimulation of the insulin-like growth factor
(IGF-1) receptor, resulting in increased protection from apoptosis (Povsic et al.
2003
). It has also been demonstrated that upon insulin stimulation,
b
-arrestin
2 mediates PKB activation through Src family tyrosine kinase in a PI3K-independent
way (Luan et al.
2009
). We have recently demonstrated that PKB in T cells, through
its PH domain, is responsible for transporting the PDE4D/
b
-arrestin/PKB complex
to the membrane upon TCR/CD28 costimulation, thus revealing a novel role for
PKB (Bjorgo et al.
2010
).
1.3.4 Functional Importance of the PKB/
-Arrestin/PDE4 Complex
b
Although the exact role of
b
-arrestin in proximal T-cell signaling is still not fully
understood, siRNA-mediated knockdown of
b
-arrestins 1 and 2 in human primary T
cells resulted in a 40 and 30% reduction in IL-2 and IFN-
g
production, respectively,
indicating that
b
-arrestin plays a positive regulatory role in proximal T-cell activa-
tion (Bjorgo et al.
2010
). The observed reduction in IL-2 production is comparable
to the effect observed by pharmacologically inhibiting PDE4 activity with rolipram,
suggesting that the main function of
b
-arrestin in proximal T-cell signaling resides
in its ability to recruit the signal termination enzyme PDE4 to lipid rafts and
thereby break the cAMP negative feedback governing T-cell receptor functioning.
Taken together, PKA and PDE4 isoforms seem to have opposing functions during
proximal T-cell signaling, thereby titrating the activation-induced response. Thus, a
novel mechanism of signaling by CD28 is revealed where CD28 through PI3K
regulates cAMP degradation in lipid rafts via recruitment of a PDE4/
b
-arrestin/
PKB complex, thereby allowing a complete T-cell activation to proceed.
T-cell proliferation and production of the cytokines IL-2, IL-4, IL-5, IFN-
g
, and
TNF-
a
are blocked by PDE4 inhibitors (Jimenez
2001
). These anti-inflammatory
