Receptor-mediated axon growth repulsion
Ephrin-A proteins which are anchored in the plasma
membrane through attachment of glycosylphosphatidylinositol
(GPI) , are the ligands for
Ephrin-A receptors, which belong to the membrane family of
receptor tyrosine kinases .
In the absence of Ephrin-A stimulation,
Ephrin-A receptors are shown to target
Ephexin exchange factor to the plasma membrane.
Ephrin-A stimulation of Ephrin-A receptors
activates exchange factors Ephexin , VAV-2  and Tiam 1 . Src-family tyrosine
kinases c-Src and Fyn are
recruited to Ephrin-A receptors after
Ephrin-A stimulation . In response to
Ephrin-A signaling Ephexin
becomes phosphorylated by c-Src  and this
phosphorylation enhances its activity toward Ras homolog gene family, member A
(RhoA) . VAV-2
is rapidly phosphorylated by c-Src upon
stimulation by Ephrin-A  and activates
Ephrin-A receptors have also been shown to signal through
the Ras-related C3 botulinum toxin substrate 1 (Rac1)
exchange factors Tiam1  and
VAV-2  to promote neurite outgrowth.
In response to Ephrin-A1 stimulation, Ras-related protein
Rap-1A is activated  and can regulate MAPK
signaling cascade by reducing c-Raf-1 activation  or by stimulation of B-Raf kinase , .
When Ephrin-A receptors are
activated, phosphorylation of Ephexin promotes its GTPase
activity toward RhoA. RhoA
downstream effector Rho-associated kinase ROCK directly
phosphorylates LIM-kinases LIMK1 and
LIMK2, which in turn phosphorylates actin-depolymerizing
factor destrin and actin-associated protein
cofilin. Activity of LIMK1 is also regulated
by p21-activated kinase 1 (PAK1) .
Cofilin and destrin both
exhibit actin-depolymerizing activity followed by
reorganization of the actin cytoskeleton , .
The F-actin-binding protein cortactin is an important
regulator of cytoskeletal dynamics, and a prominent target of various tyrosine kinases
Fer) , . Tyrosine
phosphorylation of cortactin has been suggested to reduce
its F-actin cross-linking capability .
The semaphorins family of secreted or membrane-bound proteins was identified
originally as axonal guidance factors functioning during neuronal development. The class
4 semaphorin Semaphorin 4D utilizes Plexin
B1 (transmembrane protein) as receptor. 
Plexin B1 directly interacts with exchange
factors PDZ-RhoGEF and LARG to
regulate RhoA and the growth cone morphology .
Rho6 is a member of Rho family GTPases. It is activated
by adaptor protein Grb7 and directly interacts with the
cytoplasmic domain of Plexin B1 in response to
Semaphorin 4D. Rho6 promotes
the interaction between Plexin B1 and
PDZ-RhoGEF and thereby potentiates the
PAK1 promotes activation of
actin polymerization by phosphorylation of
Arp2/3 (complex of actin-related proteins) .
c-Raf-1 kinase, a member of the MAPK pathway, is
also phosphorylated and activated by
PAK1 . Inhibition of
Pak1 by Plexin B1 is believed
to cause suppression of membrane protrusions, thus supporting the cell repulsion
response. Furthermore, active Rac1 was shown to promote cell
surface localization of Plexin B1 thus enhancing
Semaphorin 4D binding to the receptor. Thus,
Rac1 and Plexin B1 signaling
appears to be bidirectional: Rac-1 modulates
Plexin B1 activity, and Plexin
B1 modulates Rac-1 function .
Another semaphorin, Semaphorin 3A, binds to
Neuropilin-1/Plexin A1 complex
and induces repulsive responses . The active form of
Rac1 directly binds to Plexin-A1.
Activated Rac1 mediates endocytosis of the
growth cone plasma membranes and reorganization of F-actin
in neurons . Endocytosis of plasma membranes is supposed to be an
important step for growth cone collapse.
c-Fes tyrosine kinase also is implicated in
Semaphorin 3A-induced collapse .
c-Fes directly binds to the cytoplasmic region of
Plexin A1. In the resting state,
neuropilin-1 associates with Plexin-A1
and blocks the binding of c-Fes to
Plexin A1. Semaphorin 3A
binding to Neuropilin-1 permits
c-Fes to associate with and phosphorylate
Plexin A1. This tyrosine phosphorylation stimulates
repulsive action in the receptor.
c-Fes also phosphorylates collapsin response mediator
protein CRMP2 .
Fyn, a member of src-family of tyrosine kinases,
associates with Plexin A2 in response to
Semaphorin 3A and phosphorylates serine/threonine kinase
CDK5.  Activated
CDK5 phosphorylates CRMP2
. ROCK2 kinase also has been
shown to phosphorylate CRMP2 . CRMP2 binds
to tubulin heterodimers to promote microtubule assembly that is important for axonal
growth and branching . Phosphorylation of
CRMP2 reduces its tubulin-heterodimer binding and the
promotion of microtubule assembly.
CDK5 also phosphorylates the microtubule-associated
protein Tau, thereby reduces
its ability to induce tubulin microtubule formation .
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