MAG-dependent inhibition of neurite
Neurotrophins are key regulators of the fate and shape of neuronal cells. They act as
guidance cues for growth cones by remodeling actin cytoskeleton. Neurotrophins
NT-3 and NT-4/5) bind to two
structurally unrelated receptors, tyrosine kinase Trk receptors
(TrkA, TrkB and
TrkC), and Tumor necrosis factor receptor superfamily member
16 (NGFR(TNFRSF16)). Trk receptors
and NGFR(TNFRSF16) are closely associated in
Actin dynamics is controlled by Rho GTPases, which, in
turn, are regulated by opposing effects of guanine nucleotide exchange factors (GEFs) and
GTPase-activating proteins (GAPs). GAP p200RhoGAP, which is
constitutively associated with TrkA, inhibits
RhoA activity, which leads to neurite outgrowth , . GEF
RASGRF1, that is phosphorylated
and activated by TrkA, TrkB,
and TrkC, stimulates RhoA
activity, followed by inhibition of neurite outgrowth .
RhoA downstream effector ROCK
kinases directly phosphorylate kinase LIMK1, which, in turn,
phosphorylates Cofilin that exhibits
actin-depolymerizing activity , . Activated ROCK kinases subsequently inactivate
myosin light chain phosphatase (MLCP)
by phosphorylation , which attenuates myosin light
chains (MELC) and myosin
regulatory light chains (MRLC)
phosphorylation  and formation of actomyosin fibers.
Myelin-associated protein (MAG or siglec-4) is a lectin
that binds to sialylated glycoconjugates (via N-acetyl-neuraminic
acid) and mediates certain myelin-neuron cell-cell interactions.
MAG, expressed by oligodendrocytes and Schwann cells in the
nervous system, is important for maintaining the integrity of the myelin sheath.
Binding of MAG to the
NGFR(TNFRSF16), as well as its binding to
and GT1b on neuronal cells results in
activation of NGFR(TNFRSF16), that is associated with
ganglioside GT1b , .
MAG binding to NGFR(TNFRSF16)
promotes ADAM metallopeptidase domain 17 (ADAM17) - mediated
ectodomain shedding that generates NGFR(TNFRSF16) C-terminal
fragment NGFR (CTF).
Gamma-Secretase complex cleaves
NGFR (CTF) and liberates
NGFR(TNFRSF16) intracytoplasmic domain NGFR
(ICD) , . NGFR
(ICD) sequesters Rho GDP dissociation inhibitor (GDI) alpha
(RhoGDI alpha) that leads to
RhoA activation , , . These interactions induce RhoA, stimulation of
ROCK kinases, actomyosin fibers
formation, and inhibition of neurite outgrowth.
MAG can also bind to Nogo receptor
(RTN4R) in a sialic-acid-independent manner. This
interaction is functionally important for MAG-dependent
neurite inhibition. RTN4R plays central role in mediating
growth-inhibitory activities of myelin-derived proteins. Inhibitory protein
Reticulon 4 and oligodendrocyte myelin glycoprotein
(OMgp) bind to RTN4R to inhibit
axonal outgrowth . Lingo1, a nervous
system-specific transmembrane protein, binds to RTN4R and
NGFR(TNFRSF16) , which is an additional functional component
of RTN4R/ NGFR(TNFRSF16)
signaling complex . Thus,
MAG-dependent inhibition of neurite outgrowth depends on the
complex molecular interaction between MAG,
ganglioside GT1b, NGFR(TNFRSF16)
, Lingo1 and RTN4R
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