Biology Reference
In-Depth Information
Myelin-associated inhibitors
Chondroitin sulfate proteoglycans
Inhibitory
receptor complex
Inhibitory guidance molecules
RhoA
CRMP4
RhoA
GTP
GTP
RhoA
GDI
P
Cofilin
GTP
ROCK
LIMK
SSH
Cofilin
GAP
RhoA
GDI
Kalirin9
P
P
i
MLCII
GTP
P
ADP-ribose
CRMP2
RhoA
RhoA
GDI
Cethrin
GDP
Actin
RhoA regulation
Microtubule
Growth cone collapse and
outgrowth inhibition
Figure 6.1 RhoA activity is a converging factor for ligand-induced outgrowth inhibition.
Schematic illustration of the RhoA signaling pathway. RhoA activation is inhibited by
interacting with guanine-nucleotide exchange factor (GDI). Growth inhibitory proteins
signal growth cone collapse after binding to their receptor complexes. The cytoplasmic
domain of receptor components, such as p75 of the Nogo receptor complex, is involved.
For example, GDI can be sequestered away from RhoA upon p75 activation, which in
turn allows prenylated RhoA to translocate to the membrane where it can interact with
effector proteins. When GDI is released, RhoA is then activated via Rho-GEF (guanine
nucleotide exchange factor) such as Kalirin9. RhoA must be GTP bound to be active.
RhoA-GTP targets several downstream effectors such as collapsin-response mediator
proteins (CRMP2 and 4) and Rho-associated kinase (ROCK) that will modify the cytoskel-
eton. ROCK activates microtubule and actin-binding regulatory proteins such as cofilin,
myosin light chain (MLCII), and CRMP2 that will ultimately lead to growth collapse and
outgrowth inhibition. Cethrin is an enzyme that ADP-ribosylates RhoA. This inhibits the
Rho signaling pathway by stabilizing the RhoA-GDI complex in the cytosol.
proteins share the ability to bind to the same receptors, the Nogo receptor 1
(NgR1) (
Domeniconi et al., 2002; Fournier, GrandPre, & Strittmatter,
2001; Wang, Koprivica, et al., 2002
) and the paired immunoglobulin-like
receptor (PirB) (
Atwal et al., 2008
). NgR2 functions as an additional
receptor for MAG (
Venkatesh et al., 2005
). NgR1 is anchored to the
cell surface by a glycosylphosphatidylinositol moiety, so it lacks an
intracellular domain. NgR1 requires additional coreceptors to initiate
intracellular signaling following ligand binding. NgR1 signals to Rho and
