The Ephrin receptor tyrosine kinases and their Ephrin ligands play a pivotal role
during axon guidance, synaptogenesis, neuronal circuitry formation, angiogenesis and proliferation of neuronalstem cells . Ephrin
receptors and Ephrin ligands transduce intracellular responses only upon binding and
clustering in the membrane .
Ephrin-A receptors (Ephrin-A receptors 1-8) bind
glycosylphosphatidyl-anchored Ephrin-A ligands
(Ephrin-A1-5), whereas Ephrin-B receptors (Ephrin-B
receptors 1-6) bind transmembrane Ephrin-B ligands
Ephrin receptors signaling occurs through specific Guanine nucleotide exchange factors
(GEFs) and therby can activate multiple Rho family GTPases including
RhoA, Rac1 and
Ephrin-A stimulation of Ephrin-A receptors activates
three exchange factors: Ephexin , VAV-2  and
Tiam 1 . VAV-2
can also bind to Ephrin-B receptors.
In the absence of Ephrin-A stimulation,
Ephrin-A receptors alternatively engage
Ephexin at the plasma membrane. This interaction induces
Ephexin phosphorylation by c-Src
tyrosine kinase  and this phosphorylation enhances
Ephexin activity toward the GTPase
RhoA and not Rac1 or
VAV-2 is rapidly phosphorylated by c-Src
upon Ephrin stimulation of both Ephrin-A
receptors and Ephrin-B receptors  leading to RhoA activation .
RhoA-dependent signaling in both cases leads to the
growth cone retraction and collapse.
The growth cone collapse may be due to Rac1-dependent
endocytosis events. Following Ephrin-A activation,
VAV-2 induces activation of Rac1
which leads to actin cytoskeleton reorganization and endocytosis .
Ephrin-A receptors also signal through the
Rac1 exchange factor Tiam 1 to
promote neurite outgrowth .
Ephrin-A receptor 8 localizes p110gamma isoform of
phosphatidylinositol 3-kinase (PI3K cat class IB
(p110-gamma)) to the plasma membrane, thereby allowing access to lipid
substrates that facilitate integrin-mediated cell adhesion .
Src-like adapter protein SLAP binds to activated
Ephrin-A receptor 2  and this interaction
leads to the inhibiting c-Src signaling
Guanine exchange factors Kalirin and
Intersectin are downstream effectors of
Ephrin-B receptors. Kalirin and
Intersectin promote dendritic spine morphogenesis by
modulating Rac1 and CDC42
activity, respectively . Intersectin binds
to Ephrin-B receptors independently of activation by
Ephrins, while Kalirin appear to require Ephrin stimulation.
Kalirin is also phosphorylated on tyrosine residues
following Ephrin-B receptors activation .
The majority of Ephrin receptors negatively regulate the Ras/ MAP-kinase pathways in
most cell types . For instance, Ephrin-B receptor 2 via GTPase activated
protein (GAP), p120GAP, down-regulates
H-Ras activity and MAP kinase phosphorylation and induces
neurite retraction in some neuronal cell lines  However the
phosphorylation of p120GAP by
c-Src inhibites its GAP activity .
Ephrin-A1 stimulation leads to Ras-related protein
Rap-1A activation  and inhibits MAPK
signaling cascade by decreasing c-Raf-1 kinase activation
. Alternatively c-Raf-1 can also
be phosphorylated and activated by
PAK1 . Recruitment of the
adaptor proteins GRB2 and GRB10
to the activated Ephrin-B
receptor 1 also promotes MAP-kinase activation , .
Ephrin-B receptor 1 also associates with
GRB7 , that specifically activates
RHO6, a member of Rho family GTPases, and promotes axon
growth repulsion .
Ephrin-B receptor 1 and Ephrin-B receptor 2 bind adaptor
protein NCK1, thereby increasing the activity of
specifically Nck-interacting kinase HGK .
(stress-activated protein kinases) activation leads to the phosphorylation of
Paxillin by JNK, which is
essential for maintaining the dynamic cytoskeletal remodeling required for rapid cell
Ephrin receptors also maintain feedback mechanisms that
reverse signaling through their Ephrin ligands .
Src family kinases are responsible for Ephrin-B
phosphorylation upon Ephrin receptor engagement . The adaptor protein
GRB4 links Ephrin-B to a vast
signaling network that modifies cell morphology through reorganization of the actin
cytoskeleton. Phosphorylated Ephrin-B recruits the
phosphotyrosine phosphatase FAP-1, that dephosphorylates the
cytoplasmic domain of Ephrin-B .
The GTPase-activating protein RGS3,
can also transduce Ephrin-B
signaling by catalyzing the hydrolysis of GTP
to GDP in the alpha-i-subunits of G-proteins (G-protein alpha-i
family). This signaling mechanism has broad implications for cell
migratory behavior in different systems .
Ephrin-A ligands can also induce signals that modify cell
behavior. Clustering of Ephrin-A molecules with
Ephrin-A receptors recruits the Src family kinase
Fyn to lipid rafts. This is accompanied by activation of MAP
kinases and leading to an increase in cellular adhesion , .
Inhibition of Ephrin-A signaling may be modulated at the
cell surface by induction of ligand-receptor dissociation by the metalloprotease
ADAM10. Upon binding of
ADAM10 cleaves Ephrin-A2
ligands from the cell surface , serving two functions: 1)
Ephrin-A cleavage allows
Ephrin-A-receptor-bearing structures such as growth cones to
revert from cellular adhesion to repulsion, and 2) ligand cleavage leads to direct
inhibition of receptor activation .
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