Biology Reference
In-Depth Information
Furthermore, AKAPs also contribute to versatility by assembling multiprotein
signal complexes allowing signal termination by phosphoprotein phosphatases
and crosstalk between different signaling pathways (Michel and Scott
2002
; Tasken
and Aandahl
2004
). More specifically, integrating PDEs into these anchoring
complexes provide an efficient way to tightly regulate cAMP action in specific
cellular environments (reviewed in Baillie et al.
2005
; Smith and Scott
2002
).
1.1 The cAMP-PKA-Csk Inhibitory Pathway Modulates
T-Cell Immune Function
Proteins involved in proximal T-cell receptor (TCR) signaling are localized in lipid
rafts, membrane microdomains enriched in cholesterol and sphingolipids (Montixi
et al.
1998
;Xavieretal.
1998
) where they guide signal transduction through formation
of a diversity of signaling complexes (Jordan et al.
2003
). The multimeric TCR
complex is composed of two functional units: one involved in ligand binding
(
ab
) and the other in signal transduction (CD3
g
,
d
,
e
,and
z
chains). Upon TCR
engagement one of the most proximal events taking place in T cells is activation of the
Src family protein tyrosine kinases (SFKs), in particular Lck. The following phos-
phorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) present
in the CD3 subunits results in recruitment of the tandem SH2-containing tyrosine
kinase ZAP-70. ZAP-70 becomes fully active upon Lck-mediated phosphorylation
and plays an essential role with respect to further propagation of the signal down-
stream of the TCR (Zhang et al.
1998
). A complete immune response finally leads to
activation of the transcription factors nuclear factor
k
B(NF-
k
B) and nuclear factor of
activated T cells (NFAT) initiating cytokine production and T-cell proliferation
(reviewed in Rudd
1999
). To obtain proper T-cell activation and to prevent activa-
tion-induced cell death, tight regulation of the initial key enzyme Lck is required.
Phosphorylation of a conserved tyrosine residue (Y394) in the catalytic domain
of Lck gives rise to a conformational change in the activation loop of the enzyme,
thereby allowing substrate binding and catalysis to take place (Yamaguchi and
Hendrickson
1996
). In contrast, Lck is negatively regulated by phosphorylation of a
conserved C-terminal tyrosine residue (Y505) by C-terminal Src kinase (Csk),
thereby inducing an intramolecular interaction between this phospho site and the
Lck SH2 domain (Bergman et al.
1992
; Okada and Nakagawa
1989
). In resting
T cells, Csk is constitutively localized in proximity to its substrates Lck and Fyn
through docking to the hyperphosphorylated transmembrane adaptor protein Cbp/PAG
in lipid rafts (Brdicka et al.
2000
; Kawabuchi et al.
2000
). However, upon T-cell
activation, Cbp/PAG is rapidly dephosphorylated by CD45, and Csk is transiently
displaced to the cytosol (Brdicka et al.
2000
;Davidsonetal.
2003
; Torgersen et al.
2001
). Fyn-mediated phosphorylation of Cbp/PAG results in rerecruitment of Csk
and reestablishment of the inhibitory pathway (Brdicka et al.
2000
; Kawabuchi et al.
2000
). Docking of Csk to Cbp/PAG in addition to phosphorylation by PKA
