Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 59

Scaffold proteins that act in ERK signaling comprise IQ motif-containing
GTPase-activating protein-1 (IQGAP1), MAPK scaffold protein-1, Similar expres-
sion to FGF gene products (SEF), paxillin, β -arrestins, and kinase suppressor of Ras

(KSR) [ 99 ]. 11
Scaffold B-cell lymphoma protein (BCL10) operates in the JNK pathway 12

in

immunocytes. Scaffold BCL10 participates in activation of nuclear factor- B, in

addition to JNK2, in the TCR axis. It complexes with mucosa-associated lymphoid
tissue lymphoma translocation peptidase MALT1 and CARMA1 to link protein
kinase-C

κ

B downstream from antigen receptors.
The scaffold Disc large homolog DLg1 intervenes with JNK-interacting proteins
(MAPK8IP1-MAPK8IP4) in P38MAPK activation. This kinase is a sensor of pro-
inflammatory stimuli primed by cytokines.
The AHNAK 13 family of PDZ-containing scaffold proteins consist of 2 mem-
bers: Ahnak1, or desmoyokin, and Ahnak2. Protein Ahnak1 is strongly expressed
in spleen and lymph nodes, especially in splenic CD4

θ with NF κ

T cells, but weakly in
thymus [ 100 ]. In vitro, Ahnak1 fragments bind and activate phospholipase-C

+

1in
the presence of arachidonic acid. Partners of Ahnak1 include also calcium- and zinc-
binding protein S100b and the annexin-2-S100a10 complex. In cardiomyocytes,
Ahnak1 associates with the

γ

β subunit of cardiac Ca V channels at the plasma

membrane.
Scaffold Ahnak in calcium signaling binds calcium channels, phospholipase-C ,

and protein kinase-C [ 99 ]. It is phosphorylated by protein kinase-A in response to
β

γ

-adrenoreceptor stimulation. Scaffold Ahnak participates in activation of nuclear
factor of activated T cells via calmodulin and PP3 phosphatase.
In T lymphocytes, scaffolds Homer-2 and -3 inhibit nuclear factor of activated
T cells by competing with PP3 phosphatase for NFAT binding.
Initiation of the Toll-like receptor pathway involves recruitment of the adaptor
myeloid differentiation primary-response gene MyD88 to liganded TLRs. Sub-
sequently, activated IL1 receptor-associated kinases IRAK1 and IRAK4 prime
formation of a complex that contains tumor-necrosis factor receptor-associated
factor TRAF6, TRAF-interacting protein with forkhead-associated domain (TIFA),
MAP3K7, and its binding partner MAP3K7IP1 to stimulate P38MAPKs, JNKs, and
NF B[ 99 ].

The PELLINO family includes 3 known proteins in humans that can associate
with IRAK1, TRAF6, and MAP3K7 after IL1 receptor activation.

κ

11 Scaffold KSR binds 14-3-3 proteins for cytosolic sequestration. Following cell stimulation, pro-
tein phosphatase PP2a dephosphorylates and releases KSR from 14-3-3 proteins for translocation
to the plasma membrane where it can interact with activated Ras GTPase. Scaffold Connector
enhancer of kinase suppressor of Ras CNKSR1 facilitates the interaction between Raf (a MAP3K)
and KSR. KSR Isoforms include KSR1, which is highly expressed in brain, thymus and spleen, in
addition to neutrophils and macrophages and KSR2.
12 Kinase JNK is a stress-activated MAPK that acts in the regulation of lymphocyte activation and
development.
13 Hebrew ahnak: giant.