Biomedical Engineering Reference
In-Depth Information
TCR ligation
P
Src/Syk
kinases
CARMA1
PDK1
PI3K
PKCθ
BCL-10
MALT1
Caspase 8
TRAF6
B pathway.
TCR triggering
leads to engagement of receptor associated tyrosine kinases of the Src and Syk families,
controlling activation of PI3K. PI3K-dependent generation of membrane associated phospho-
lipids leads to recruitment of PDK1, which may directly phosphorylate and activate PKC
FIGURE 3.4
Schematic representation of the TCR-induced NF-
κ
θ
and control further recruitment of CARMA1. Assembly of these molecules in lipid rafts
initiates recruitment of BCL10 and MALT1, and possibly TRAF6/TAK1. The molecular
mechanism of IKK activation is unclear. It may involve direct ubiquitination of NEMO, or
TRAF6-dependent ubiquitination and activation of TAK1, comparable to the mechanism
overall model depicted here for TCR signaling can also be applied to BCR signaling (see
Chapter 7
).
dependent PKC
activation depends on PDK1 (3-phosphoinositide-dependent
kinase-1), which may directly phosphorylate PKC
θ
at its activation loop [111].
PDK1 was also found to interact with CARMA1 by coimmunoprecipitation and to
be required for IKK recruitment [111]. As such, PDK1 seems to serve a central role
in TCR signaling, initiating the recruitment of several critical signaling molecules
and IKK into close proximity [112]. The paracaspase MALT1 directly interacts with
BCL10 and activates NF-
θ
B, when
coexpressed with BCL10 [113]. The mechanism
of IKK activation is still not entirely clear. The role of BCL10 may be the recruitment
and possibly oligomerization of MALT1, which seems to be an important
κ
